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Transneuronal Propagation of Pathologic α-Synuclein from the Gut to the Brain Models Parkinson’s Disease
Abstract
Analysis of human pathology led Braak to postulate that α-synuclein (α-syn) pathology could spread from the gut to brain via the vagus nerve. Here, we test this postulate by assessing α-synucleinopathy in the brain in a novel gut-to-brain α-syn transmission mouse model, where pathological α-syn preformed fibrils were injected into the duodenal and pyloric muscularis layer. Spread of pathologic α-syn in brain, as assessed by phosphorylation of serine 129 of α-syn, was observed first in the dorsal motor nucleus, then in caudal portions of the hindbrain, including the locus coeruleus, and much later in basolateral amygdala, dorsal raphe nucleus, and the substantia nigra pars compacta. Moreover, loss of dopaminergic neurons and motor and non-motor symptoms were observed in a similar temporal manner. Truncal vagotomy and α-syn deficiency prevented the gut-to-brain spread of α-synucleinopathy and associated neurodegeneration and behavioral deficits. This study supports the Braak hypothesis in the etiology of idiopathic Parkinson's disease (PD).
... However, another study discussed clinical evidence that the case is not very clear (Tysnes et al., 2015). In addition, experimental evidence in rodents showed that the injection of the aggregated form of αsynuclein into the intestinal wall could promote the accumulation of endogenous α-synuclein (Kim et al., 2019;Van Den Berge et al., 2019). These evidence indicated that α-synuclein aggregates contributed to the accumulation of aggregated α-synuclein in various brain regions through vagus nerve transmission. ...
... These evidence indicated that α-synuclein aggregates contributed to the accumulation of aggregated α-synuclein in various brain regions through vagus nerve transmission. This transmission was time-specific and region-dependent (Kim et al., 2019). The gastrointestinal tract is innervated by parasympathetic vagal and sympathetic non-vagal pathway. ...
... Immunohistochemical detection in PD transgenic mice showed that a few months before the loss of striatal dopaminergic neurons, age-dependent α-synuclein-GFP was progressively expressed and accumulated in the Meissner and Auerbach plexus of the colon (Chen et al., 2018a). Some studies have shown that different forms of αsynuclein can be transmitted to the brain through the vagus nerve, which may be the mechanism of prion-like transmission of α-synuclein in PD and related diseases (Zhong et al., 2017;Kim et al., 2019;Liu et al., 2021a). This evidence all shows that the abnormal intestinal α-synuclein deposition is earlier than the occurrence of degenerative diseases of the CNS (Hilton et al., 2014). ...
Parkinson's disease (PD) is the second most common chronic progressive neurodegenerative disease. The main pathological features are progressive degeneration of neurons and abnormal accumulation of α-synuclein. At present, the pathogenesis of PD is not completely clear, and many changes in the intestinal tract may be the early pathogenic factors of PD. These changes affect the central nervous system (CNS) through both nervous and humoral pathways. α-Synuclein deposited in the intestinal nerve migrates upward along the vagus nerve to the brain. Inflammation and immune regulation mediated by intestinal immune cells may be involved, affecting the CNS through local blood circulation. In addition, microorganisms and their metabolites may also affect the progression of PD. Therefore, paying attention to the multiple changes in the intestinal tract may provide new insight for the early diagnosis and treatment of PD.
... To circumvent this issue, we examined the hippocampus of our mice. Propagation of α-Syn aggregates from the SN to the hippocampus over time is well known [32][33][34]. Our Nissl staining in the hippocampus showed that hippocampal neuronal loss was minimal even if α-Syn pathology was observed. ...
... AAV-mediated α-Syn overexpression resulted in pS129-α-Syn expression in the injection site. However, as dopaminergic neuronal loss in the SN increases, pS129 staining is concomitantly reduced [33]. This made it difficult to use pS129-α-Syn as an indicator of therapeutic efficacy of NXP031 for α-Syn aggregation in the SN. ...
... To circumvent this problem, we investigated other brain regions relatively resistant to α-Syn-mediated cell death. As previous studies have shown that α-Syn aggregates propagate from the midbrain to the hippocampus [32][33][34], we performed pS129-α-Syn staining in this region. Interestingly, the AAV-WT-α-Syn group showed significantly increased pS129-α-Syn levels compared to the AAV-GFP group even in this more distal region, which was blocked by NXP031 treatments, further highlighting the therapeutic potential of this compound. ...
Parkinson's disease (PD) is a neurodegenerative disease characterized by inclusions of aggregated α-synuclein (α-Syn). Oxidative stress plays a critical role in nigrostriatal degeneration and is responsible for α-Syn aggregation in PD. Vitamin C or ascorbic acid acts as an effective antioxidant to prevent free radical damage. However, vitamin C is easily oxidized and often loses its physiological activity, limiting its therapeutic potential. The objective of this study was to evaluate whether NXP031, a new compound we developed consisting of Aptamin C and Vitamin C, is neuroprotective against α-synucleinopathy. To model α-Syn induced PD, we stereotactically injected AAV particles overexpressing human α-Syn into the substantia nigra (SN) of mice. One week after AAV injection, NXP031 was administered via oral gavage every day for eight weeks. We found that oral administration of NXP031 ameliorated motor deficits measured by the rotarod test and prevented the loss of nigral dopaminergic neurons caused by WT-α-Syn overexpression in the SN. Also, NXP031 blocked the propagation of aggregated α-Syn into the hippocampus by alleviating oxidative stress. These results indicate that NXP031 can be a potential therapeutic for PD.
... Locus coeruleus is affected in the early stage of PD pathology spread, which leads to noradrenergic content loss of up to 70% in the brain [71][72][73][74][75][76] , resulting in decreased noradrenergic projection to cerebellum 77 , thalamus 78 , and motor cortex 78 in PD. In other words, all structures involved in CTC circuits suffer the loss of noradrenergic input in PD. ...
... A possible explanation for the above differences in responsiveness of tremor to dopamine between PD-RS and PD-RP may be as follows: Because different brain regions may be affected as the PD pathology progresses 11,[53][54][55][56][73][74][75][76][77][78] . At different disease stages, brain regions responsible for tremor may be affected by PD pathology to different degrees. ...
Tremor is one of the core symptoms of Parkinson’s disease (PD), but its mechanism is poorly understood. The cerebellum is a growing focus in PD-related researches and is reported to play an important role in tremor in PD. The cerebellum may participate in the modulation of tremor amplitude via cerebello-thalamo-cortical circuits. The cerebellar excitatory projections to the ventral intermediate nucleus of the thalamus may be enhanced due to PD-related changes, including dopaminergic/non-dopaminergic system abnormality, white matter damage, and deep nuclei impairment, which may contribute to dysregulation and resistance to levodopa of tremor. This review summarized the pathological, structural, and functional changes of the cerebellum in PD and discussed the role of the cerebellum in PD-related tremor, aiming to provide an overview of the cerebellum-related mechanism of tremor in PD.
... Several animal studies have reported the spread of α-synuclein pathology from the gut to the brain, and pathological changes in the CNS can be observed after the injection of α-synuclein into the intestinal wall [94][95][96]. However, the exact route through which pathological deposits of α-synuclein may spread to the brain remains vastly hypothetical. ...
... According to Braak's original hypothesis, environmental factors may contribute, triggering the pathological process via the olfactory bulb or the intestinal nerve plexus [97]. Supporting this theory, vagotomy can prevent the transmission of pathological alpha-synuclein to the CNS in animal models [95]. ...
The gut-brain axis (GBA) is a complex interactive network linking the gut to the brain. It involves the bidirectional communication between the gastrointestinal and the central nervous system, mediated by endocrinological, immunological, and neural signals. Perturbations of the GBA have been reported in many neurodegenerative diseases, suggesting a possible role in disease pathogenesis, making it a potential therapeutic target. The gut microbiome is a pivotal component of the GBA, and alterations in its composition have been linked to GBA dysfunction and CNS inflammation and degeneration. The gut microbiome might influence the homeostasis of the central nervous system homeostasis through the modulation of the immune system and, more directly, the production of molecules and metabolites. Small clinical and preclinical trials, in which microbial composition was manipulated using dietary changes, fecal microbiome transplantation, and probiotic supplements, have provided promising outcomes. However, results are not always consistent, and large-scale randomized control trials are lacking. Here, we give an overview of how the gut microbiome influences the GBA and could contribute to disease pathogenesis in neurodegenerative diseases.
... Evidence from animal and cell models also support the cell-to-cell prion-like transmission of pathological alpha-synuclein that leads to Lewy pathology and dopaminergic neuronal loss [44,45]. Supporting these findings from human PD patients, data from rodent and non-human primate models have shown that intra-intestinal injection of alpha-synuclein fibrils triggers aggregation of phosphorylated alphasynuclein at the dorsal motor nucleus of the vagus nerve, followed by the locus coeruleus and substantia nigra via the vagus nerve in a longitudinal follow-up [32,46,47]. The pathological alpha-synuclein spread, dopaminergic neuronal degeneration, and motor dysfunction were mitigated by vagotomy [46,48,49]. ...
... Supporting these findings from human PD patients, data from rodent and non-human primate models have shown that intra-intestinal injection of alpha-synuclein fibrils triggers aggregation of phosphorylated alphasynuclein at the dorsal motor nucleus of the vagus nerve, followed by the locus coeruleus and substantia nigra via the vagus nerve in a longitudinal follow-up [32,46,47]. The pathological alpha-synuclein spread, dopaminergic neuronal degeneration, and motor dysfunction were mitigated by vagotomy [46,48,49]. Consistently, epidemiological studies using Swedish and Danish registries have demonstrated that truncal vagotomy decreases the risk of developing PD by 15-22%, further supporting that the vagus nerve is involved in the transmission of pathological alpha-synuclein in the pathogenesis of PD [50,51]. ...
Parkinson's disease (PD) is the second most common neurodegenerative disease attributed to the synergistic effects of genetic risk and environmental stimuli. Although PD is characterized by motor dysfunction resulting from intraneuronal alpha-synuclein accumulations, termed Lewy bodies, and dopaminergic neuronal degeneration in the substantia nigra, multiple systems are involved in the disease process, resulting in heterogenous clinical presentation and progression. Genetic predisposition to PD regarding aberrant immune responses, abnormal protein aggregation, autophagolysosomal impairment, and mitochondrial dysfunction leads to vulnerable neurons that are sensitive to environmental triggers and, together, result in neuronal degeneration. Neuropathology studies have shown that, at least in some patients, Lewy bodies start from the enteric nervous system and then spread to the central dopaminergic neurons through the gut-brain axis, suggesting the contribution of an altered gut microenvironment in the pathogenesis of PD. A plethora of evidence has revealed different gut microbiomes and gut metabolites in patients with PD compared to unaffected controls. Chronic gut inflammation and impaired intestinal barrier integrity have been observed in human PD patients and mouse models of PD. These observations led to the hypothesis that an altered gut microenvironment is a potential trigger of the PD process in a genetically susceptible host. In this review, we will discuss the complex interplay between genetic factors and gut microenvironmental changes contributing to PD pathogenesis.
... Phosphorylated and misfolded α-synuclein is a major constituent of Lewy body inclusions and Lewy neurites in PD and related brain diseases such as αsynucleinopathy [3]. Approximately 80% of PD patients progressively manifest cognitive deficits over 15 years since the diagnosis of motor dysfunction, which is associated with the pathological propagation of Lewy pathologies from the midbrain towards the limbic and cortical brain areas [4]. Despite the extensive pathological involvement of diverse brain regions in PD patients, currently available therapies focus on mitigating overt symptoms mainly by supplementing the responsible neurotransmitters or augmenting specific receptor-regulated signaling pathways. ...
... α-Synuclein aggregation pathologies are characterized by progressive impairment of brain function mediated by various brain subregions. According to Braak's theory, which was supported by experimental data [4,9,15], α-synuclein aggregation can be initiated in the intestinal peripheral nervous system or olfactory nerve; this Lewy pathology can then propagate to higher brain structures in the central nervous system through retrograde transmission. In-deed, targeting α-synuclein aggregation could be beneficial for terminating Lewy pathology propagation at any Braak stages. ...
Pathological protein inclusion formation and propagation are the main causes of neuronal dysfunction in diverse neurodegenerative diseases; therefore, current disease-modifying therapeutic strategies have targeted this disease protein aggregation process. Recently, we reported that peucedanocoumarin III (PCiii) is a promising therapeutic compound with the ability to disaggregate α-synuclein inclusion and protect dopaminergic neurons in Parkinson’s disease (PD). Here, we found that trans-4′-acetyl-3′-tigloylkhellactone (racemic peucedanocoumarin IV [PCiv]), a structural isomer of PCiii with a higher synthetic yield presented a strong anti-aggregate activity to a degree comparable to that of PCiii. PCiv retained effective inhibitory function against β-sheet aggregate-mimic β23 cytotoxicities and potently prevented α-synucleinopathy in α-synuclein preformed fibril (PFF)-treated mice cortical neurons. In detailed pharmacokinetic profiling of PCiv, oral administration of PCiv in rats exhibited an approximately 97-min half-life and 10% bioavailability. Moreover, tissue distribution analysis revealed favorable profiles of brain penetration with a 6.4 brain-to-plasma concentration ratio. The therapeutic efficacy of PCiv was further evaluated in a sporadic PD mouse model with a combinatorial co-injection of α-synuclein preformed fibril and recombinant adeno-associated virus expressing α-synuclein. Motor dysfunctions induced in this combinatorial α-synucleinopathy PD mouse model was almost completely rescued by PCiv diet administration, and this therapeutic effect is consistent with the marked prevention of dopaminergic neuron loss and suppression of α-synuclein aggregation. Taken together, our translational study suggests that PCiv is advantageous as a therapeutic agent for neurodegenerative diseases, especially with its good synthetic yield, high brain distribution, and anti-aggregate activity. PCiv may be useful in the manamanagement of α-synuclein inclusion formation and propagation at different stages of PD.
... Holmqvist et al. showed that injection of human a-synuclein fibrils into the gut tissue of healthy rodents is sufficient to induce aggregated a-synuclein pathology within the vagus nerve and brainstem, which provided the first direct experimental evidence that a-synuclein can propagate from the gut to the brain (28). Recently, another study also demonstrated gut-to-brain spread of pathological a-synuclein fibrils following their injection into the mouse muscularis layer of the pylori and duodenum, but not when the mice were subjected to truncal vagotomy following a-synuclein fibril injection (29). ...
... The interaction between a-synuclein aggregation and the gut microbiota in PD is receiving increasing attention. Recent evidence suggests that a-synuclein aggregation may begin in the gut and gradually travel to the brain along the vagus nerve, with altered gut microbiota being a potential trigger for asynuclein misfolding (29,113,114). Gut dysbiosis cause misfolding and abnormal aggregation of a−synuclein in the intestine, which can be transported from the ENS to CNS. Several reports have observed that gut microbiota play an important role in regulating misfolded and abnormal aggregation of a-synuclein and the gut-brain axis (115). ...
Parkinson's disease (PD) is the second most common neurodegenerative disease characterized by motor dysfunction. Growing evidence has demonstrated that gut dysbiosis is involved in the occurrence, development and progression of PD. Numerous clinical trials have identified the characteristics of the changed gut microbiota profiles, and preclinical studies in PD animal models have indicated that gut dysbiosis can influence the progression and onset of PD via increasing intestinal permeability, aggravating neuroinflammation, aggregating abnormal levels of a-synuclein fibrils, increasing oxidative stress, and decreasing neurotransmitter production. The gut microbiota can be considered promising diagnostic and therapeutic targets for PD, which can be regulated by probiotics, psychobiotics, prebiotics, synbiotics, postbiotics, fecal microbiota transplantation, diet modifications, and Chinese medicine. This review summarizes the recent studies in PD-associated gut microbiota profiles and functions, the potential roles, and mechanisms of gut microbiota in PD, and gut microbiota-targeted interventions for PD. Deciphering the underlying roles and mechanisms of the PD-associated gut microbiota will help interpret the pathogenesis of PD from new perspectives and elucidate novel therapeutic strategies for PD.
... In addition to the central nervous system (CNS), the aggregates of α-syn fibrils were also found in the enteric nervous system (ENS) in patients with PD (Braak et al., 2006;Beach et al., 2016;Zhong et al., 2017;Manfredsson et al., 2018). New evidence strongly suggests that α-syn fibrils could spread from the ENS toward the brain and propagate across from one region to others of the brain (Kim et al., 2019;Challis et al., 2020;Gómez-Benito et al., 2020). There is an inevitable relationship between the production of intestinal α-syn and the intestinal microenvironment. ...
... The concept of the brain-gut axis has been further developed and enriched in the past decade, and accumulating evidence indicated that brain-gut interaction plays an important role in the pathological formation of neurodegenerative diseases (Arotcarena et al., 2020). Because of the complex influencing factors involved, the influence of the brain-gut axis on neurodegenerative diseases is still unclear (Kim et al., 2019). ...
Multiple factors such as genes, environment, and age are involved in developing Parkinson’s disease (PD) pathology. However, how various factors interact to cause PD remains unclear. Here, 3-month and 9-month-old hα-syn +/− mice were treated with low-dose rotenone for 2 months to explore the mechanisms that underline the environment–gene–age interaction in the occurrence of PD. We have examined the behavior of mice and the PD-like pathologies of the brain and gut. The present results showed that impairments of the motor function and olfactory function were more serious in old hα-syn +/– mice with rotenone than that in young mice. The dopaminergic neuron loss in the SNc is more in old hα-syn +/– mice with rotenone than in young mice. Expression of hα-syn +/– is increased in the SNc of hα-syn +/– mice following rotenone treatment for 2 months. Furthermore, the number of activated microglia cells increased in SNc and accompanied the high expression of inflammatory cytokines, namely, TNF-α and IL-18 in the midbrain of old hα-syn +/– mice treated with rotenone. Meanwhile, we found that after treatment with rotenone, hα-syn positive particles deposited in the intestinal wall, intestinal microflora, and T lymphocyte subtypes of Peyer’s patches changed, and intestinal mucosal permeability increased. Moreover, these phenomena were age-dependent. These findings suggested that rotenone aggravated the PD-like pathologies and affected the brain and gut of human α-syn +/– transgenic mice in an age-dependent manner.
... Postmortem studies have found α-synuclein pathology in the enteric nervous system during early stages of PD (5), and gastrointestinal dysfunction is often among the first disease symptoms (6). Rodent models have recapitulated the spread of α-synuclein pathology with associated neurodegeneration and motor deficits after oral administration (7) or gastrointestinal injection (8,9) of recombinant α-synuclein pre-formed fibrils (PFFs). ...
... Several studies have also demonstrated the spread of α-synuclein pathology from peripheral sites to the CNS, using intravenous (25), intramuscular (26), or intraperitoneal (27) injections of recombinant α-synuclein aggregates into rodents. More recently, oral administration or gastrointestinal injection of PFFs in mice was shown to recapitulate gut-to-brain α-synuclein spread and PD-like disease (7,8,9). ...
Parkinson's disease (PD) is a debilitating neurodegenerative disorder characterized by progressive motor decline and the aggregation of α-synuclein protein. Growing evidence suggests that α-synuclein aggregates may spread from neurons of the digestive tract to the central nervous system in a prion-like manner, yet the mechanisms of α-synuclein transmission and neurotoxicity remain poorly understood. Animal models that are amenable to high-throughput investigations are needed to facilitate the discovery of disease mechanisms. Here we describe the first Caenorhabditis elegans models in which feeding with α-synuclein preformed fibrils (PFFs) induces dopaminergic neurodegeneration, prion-like seeding of aggregation of human α-synuclein expressed in the host, and an associated motor decline. RNAi-mediated knockdown of the C. elegans syndecan sdn-1, or other enzymes involved in heparan sulfate proteoglycan synthesis, protected against PFF-induced α-synuclein aggregation, motor dysfunction, and dopamine neuron degeneration. This work offers new models by which to investigate gut-derived α-synuclein spreading and propagation of disease.
... Animal experiments have confirmed that α-syn can be transported to the brain through the blood-brain barrier (BBB) (Holmqvist et al., 2014;Kim et al., 2019). Truncal vagotomy and α-syn deficiency reduce α-syn associated neurodegeneration, which is evidence of α-syn spreading from the gut to the brain (Svensson et al., 2015). ...
... The vagus nerve is one of the largest nerves connecting the GI tract and the brain, and it is a crucial pathway for the transmission of β-syn between the periphery and the brain (Figure 3). In animal experiments, α-syn can spread from the duodenum to the brain stem and then from the brain stem to the stomach via the vagus nerve (Ulusoy et al., 2017;Uemura et al., 2018;Kim et al., 2019;Van Den Berge et al., 2019). Although the level of α-syn used in the above was much higher than in PD, it may not accurately mimic human pathophysiology, but the existence of this pathway had been explored to some extent. ...
Gastrointestinal (GI) symptoms represented by constipation were significant non-motor symptoms of Parkinson’s disease (PD) and were considered early manifestations and aggravating factors of the disease. This paper reviewed the research progress of the mechanism of the gut-brain axis (GBA) in PD and discussed the roles of α-synuclein, gut microbiota, immune inflammation, neuroendocrine, mitochondrial autophagy, and environmental toxins in the mechanism of the GBA in PD. Treatment of PD based on the GBA theory has also been discussed, including (1) dietary therapy, such as probiotics, vitamin therapy, Mediterranean diet, and low-calorie diet, (2) exercise therapy, (3) drug therapy, including antibiotics; GI peptides; GI motility agents, and (4) fecal flora transplantation can improve the flora. (5) Vagotomy and appendectomy were associated but not recommended.
... At the beginning of the 2000s, human postmortem studies led by Braak and colleagues suggested for the first time that such α-Syn pathology is not confined to the CNS and is also detectable in the ENS [56][57][58], which is a division of the peripheral nervous system that controls the gastrointestinal system [59]. The evidence of α-Syn pathology also in this system lent support to the theory that PD pathology could be initiated in the ENS [36] and that it could be spread from the gastrointestinal tract to the midbrain via the vagus nerve, resulting in the selective death of SNc dopamine neurons [57,60] (see Figure 1). ...
... Furthermore, α-Syn aggregations were observed in animal models during both early and advanced PD [61,71,72]. Strikingly, truncal vagotomy and α-Syn deficiency prevented the spread of α-Syn aggregations from the gut to the brain and associated neurodegeneration and behavioral deficits in mice models of PD [60]. ...
An emerging body of literature suggests that long-term gut inflammation may be a silent driver of Parkinson’s disease (PD) pathogenesis. Importantly, specific nutritive patterns might improve gut health for PD risk reduction. Here, we review the current literature on the nutritive patterns and inflammatory markers as a predictor for early detection of PD. This knowledge might be used to foster the detection of early nutritive patterns and preclinical biomarkers to potentially alter PD development and progression.
... A pathoanatomical study of LBD has found that alpha-synuclein aggregated in the distal esophagus, stomach, and colon [57]. Braak et al. hypothesized that abnormal alpha-synuclein accumulation would begin in the gut and further progress to the brain in a prion-like manner through the vagus nerve, which has been confirmed by animal experiments [58][59][60]. ...
Background
The current genome-wide association study (GWAS) of Lewy body dementia (LBD) suffers from low power due to a limited sample size. In addition, the genetic determinants underlying LBD and the shared genetic etiology with Alzheimer’s disease (AD) and Parkinson’s disease (PD) remain poorly understood.
Methods
Using the largest GWAS summary statistics of LBD to date (2591 cases and 4027 controls), late-onset AD (86,531 cases and 676,386 controls), and PD (33,674 cases and 449,056 controls), we comprehensively investigated the genetic basis of LBD and shared genetic etiology among LBD, AD, and PD. We first conducted genetic correlation analysis using linkage disequilibrium score regression (LDSC), followed by multi-trait analysis of GWAS (MTAG) and association analysis based on SubSETs (ASSET) to identify the trait-specific SNPs. We then performed SNP-level functional annotation to identify significant genomic risk loci paired with Bayesian fine-mapping and colocalization analysis to identify potential causal variants. Parallel gene-level analysis including GCTA-fastBAT and transcriptome-wide association analysis (TWAS) was implemented to explore novel LBD-associated genes, followed by pathway enrichment analysis to understand underlying biological mechanisms.
Results
Pairwise LDSC analysis found positive genome-wide genetic correlations between LBD and AD (rg = 0.6603, se = 0.2001; P = 0.0010), between LBD and PD (rg = 0.6352, se = 0.1880; P = 0.0007), and between AD and PD (rg = 0.2136, se = 0.0860; P = 0.0130). We identified 13 significant loci for LBD, including 5 previously reported loci (1q22, 2q14.3, 4p16.3, 4q22.1, and 19q13.32) and 8 novel biologically plausible genetic associations (5q12.1, 5q33.3, 6p21.1, 8p23.1, 8p21.1, 16p11.2, 17p12, and 17q21.31), among which APOC1 (19q13.32), SNCA (4q22.1), TMEM175 (4p16.3), CLU (8p21.1), MAPT (17q21.31), and FBXL19 (16p11.2) were also validated by gene-level analysis. Pathway enrichment analysis of 40 common genes identified by GCTA-fastBAT and TWAS implicated significant role of neurofibrillary tangle assembly (GO:1902988, adjusted P = 1.55 × 10⁻²).
Conclusions
Our findings provide novel insights into the genetic determinants of LBD and the shared genetic etiology and biological mechanisms of LBD, AD, and PD, which could benefit the understanding of the co-pathology as well as the potential treatment of these diseases simultaneously.
... In other words, dietary GABA enhances the postprandial activation of vagal afferents, thereby potentiating postprandial satiation. Recent growing evidence has indicated that gut-brain signal-related vagal afferents and gut microbiota influence emotional behaviors [52][53][54][55]; thus, dietary GABA might act on the gutbrain axis to treat stress-related disorders. By clarifying the detailed mechanism of vagal afferent activation by dietary GABA, the control of vagal nerve activity by dietary GABA might become a useful tool for improving brain functions including feeding, metabolism, and other mental functions. ...
Gamma-aminobutyric acid (GABA) is present in the mammalian brain as the main inhibitory neurotransmitter and in foods. It is widely used as a supplement that regulates brain function through stress-reducing and sleep-enhancing effects. However, its underlying mechanisms remain poorly understood, as it is reportedly unable to cross the blood–brain barrier. Here, we explored whether a single peroral administration of GABA affects feeding behavior as an evaluation of brain function and the involvement of vagal afferent nerves. Peroral GABA at 20 and 200 mg/kg immediately before refeeding suppressed short-term food intake without aversive behaviors in mice. However, GABA administration 30 min before refeeding demonstrated no effects. A rise in circulating GABA concentrations by the peroral administration of 200 mg/kg GABA was similar to that by the intraperitoneal injection of 20 mg/kg GABA, which did not alter feeding. The feeding suppression by peroral GABA was blunted by the denervation of vagal afferents. Unexpectedly, peroral GABA alone did not alter vagal afferent activities histologically. The coadministration of a liquid diet and GABA potentiated the postprandial activation of vagal afferents, thereby enhancing postprandial satiation. In conclusion, dietary GABA activates vagal afferents in collaboration with meals or meal-evoked factors and regulates brain function including feeding behavior.
... The non-motor symptoms of PD, such as constipation, impaired olfaction, and rapid eye movement sleep behavior disorders, are frequently present before the onset of motor symptoms, which might be explained by the accumulation of alpha-synuclein in the peripheral nervous system before spreading to the substantia nigra 2 . The progressive spreading of alpha-synuclein from peripheral nerves into the brain was previously proposed in neuropathologic studies and also demonstrated in mouse models, where injection of preformed alpha-synuclein fibrils into the gastric muscular layers resulted in the spread of pathologic alphasynuclein into the brain, while truncal vagotomy prevented the spread 3,4 . These findings led to the hypothesis that the pathology of PD may initiate in the gut 5 . ...
Although several studies have identified a distinct gut microbial composition in Parkinson’s disease (PD), few studies have investigated the oral microbiome or functional alteration of the microbiome in PD. We aimed to investigate the connection between the oral and gut microbiome and the functional changes in the PD-specific gut microbiome using shotgun metagenomic sequencing. The taxonomic composition of the oral and gut microbiome was significantly different between PD patients and healthy controls (P = 0.003 and 0.001, respectively). Oral Lactobacillus was more abundant in PD patients and was associated with opportunistic pathogens in the gut (FDR-adjusted P < 0.038). Functional analysis revealed that microbial gene markers for glutamate and arginine biosynthesis were downregulated, while antimicrobial resistance gene markers were upregulated in PD patients than healthy controls (all P < 0.001). We identified a connection between the oral and gut microbiota in PD, which might lead to functional alteration of the microbiome in PD.
... The enteroendocrine cells of the intestinal epithelium are connected to the enteric nerve and are potential accumulation sites of the α-synuclein(Chandra et al., 2017). Misfolded aggregates of α-synuclein appear earlier in the patient's ENS and then enter the brainstem via the dorsal motor nucleus of the vagus in the medulla, which is accompanied by alterations in intestinal microbes(Kim et al., 2019;Manfredsson et al., 2018;Derkinderen et al., 2020;Uemura et al., 2018), eventually giving ...
Background
Neurodegenerative diseases are chronic, currently incurable, diseases of the elderly, which are characterized by protein misfolding and neuronal damage. Fucoxanthin, derived from marine brown algae, presents a promising candidate for the development of effective therapeutic strategies.
Scope
The relationship between neurodegenerative disease management and fucoxanthin has not yet been clarified. This study focuses on the fundamental mechanisms and targets of fucoxanthin in Alzheimer's and Parkinson's disease management, showing that communication between the brain and the gut contributes to neurodegenerative diseases and early diagnosis of ophthalmic diseases. This paper also presents, new insights for future therapeutic directions based on the integrated application of artificial intelligence.
Conclusion
Fucoxanthin primarily binds to amyloid fibrils with spreading properties such as Aβ, tau, and α-synuclein to reduce their accumulation levels, alleviate inflammatory factors, and restore mitochondrial membranes to prevent oxidative stress via Nrf2 and Akt signaling pathways, involving reduction of specific secretases. In addition, fucoxanthin may serve as a preventive diagnosis for neurodegenerative diseases through ophthalmic disorders. It can modulate gut microbes and has potential for the alleviation and treatment of neurodegenerative diseases.
... Third, the level of aSyn aggregates in the cerebrospinal fluid (CSF) and skin biopsies distinguishes PD patients from controls with high accuracy [34][35][36] . Fourth, several animal models show that overexpression of aSyn (the wild-type form or diseaseassociated mutant forms) or inoculation of aSyn into the central nervous system (CNS) and peripheral tissues induces aSyn pathology formation and/or pathology spreading into brain regions that are affected in PD and other synucleinopathies [37][38][39] . These observations, combined with the findings that aSyn aggregation and pathology spreading in rodent models increases with increasing aSyn levels, point to aSyn as a central player in PD pathogenesis [40][41][42][43] . ...
Parkinson’s disease (PD), the second most common progressive neurodegenerative disease, develops and progresses for 10–15 years before the clinical diagnostic symptoms of the disease are manifested. Furthermore, several aspects of PD pathology overlap with other neurodegenerative diseases (NDDs) linked to alpha-synuclein (aSyn) aggregation, also called synucleinopathies. Therefore, there is an urgent need to discover and validate early diagnostic and prognostic markers that reflect disease pathophysiology, progression, severity, and potential differences in disease mechanisms between PD and other NDDs. The close association between aSyn and the development of pathology in synucleinopathies, along with the identification of aSyn species in biological fluids, has led to increasing interest in aSyn species as potential biomarkers for early diagnosis of PD and differentiate it from other synucleinopathies. In this review, we (1) provide an overview of the progress toward mapping the distribution of aSyn species in the brain, peripheral tissues, and biological fluids; (2) present comparative and critical analysis of previous studies that measured total aSyn as well as other species such as modified and aggregated forms of aSyn in different biological fluids; and (3) highlight conceptual and technical gaps and challenges that could hinder the development and validation of reliable aSyn biomarkers; and (4) outline a series of recommendations to address these challenges. Finally, we propose a combined biomarker approach based on integrating biochemical, aggregation and structure features of aSyn, in addition to other biomarkers of neurodegeneration. We believe that capturing the diversity of aSyn species is essential to develop robust assays and diagnostics for early detection, patient stratification, monitoring of disease progression, and differentiation between synucleinopathies. This could transform clinical trial design and implementation, accelerate the development of new therapies, and improve clinical decisions and treatment strategies.
... Rotarod Test. As previously reported, low speed: the instrument is set to accelerate from 0 rpm to 10 rpm within 30 s and maintained to 300 s; high speed: the instrument is set to accelerate from 4 rpm to 40 rpm and maintained to 300 s within 120 s [39,40]. The mice will be placed on a rotating rod apparatus, and preoperative training will continue for 5 days. ...
The infiltration of blood components into the brain parenchyma through the lymphoid system is an important cause of subarachnoid hemorrhage injury. AQP4, a water channel protein located at the astrocyte foot, has been reported to regulate blood–brain barrier integrity, and its polarization is disrupted after SAH. Neuronal ferroptosis is involved in subarachnoid hemorrhage- (SAH-) induced brain injury, but the inducing factors are not completely clear. Transferrin is one of the inducing factors of ferroptosis. This study is aimed at researching the role and mechanism of AQP4 in brain injury after subarachnoid hemorrhage in mice. An experimental mouse SAH model was established by endovascular perforation. An AAV vector encoding AQP4 with a GFAP-specific promoter was administered to mice to achieve specific overexpression of AQP4 in astrocytes. PI staining, Fer-1 intervention, and transmission electron microscopy were used to detect neuronal ferroptosis, and dextran (40 kD) leakage was used to detect BBB integrity. Western blot analysis of perfused brain tissue protein samples was used to detect transferrin infiltration. First, neuronal ferroptosis 24 h after SAH was observed by PI staining and Fer-1 intervention. Second, a significant increase in transferrin infiltration was found in the brain parenchyma 24 h after SAH modeling, while transferrin content was positively correlated with neuronal ferroptosis. Then, we observed that AQP4 overexpression effectively improved AQP depolarization and BBB injury induced by SAH and significantly reduced transferrin infiltration and neuronal ferroptosis after SAH. Finally, we found that AQP4 overexpression could effectively improve the neurobehavioral ability of SAH mice, and the neurobehavioral ability was negatively correlated with transferrin brain content. Taken together, these data indicate that overexpression of AQP4 in the mouse brain can effectively improve post-SAH neuronal ferroptosis and brain injury, at least partly by inhibiting transferrin infiltration into the brain parenchyma in the glymphatic system.
... Furthermore, growing evidence showed that α-Syn may be transmitted in a prion-like manner (54-57). Recent studies also supported Braak's hypothesis in the etiology of PD and the prion-like theory (58), and indicated that the prion-like seeding activity of aberrant α-Syn may be related with its post-translational modifications (such as, carboxy-truncation) or oligomerization (59,60). Several factors, such as antibiotics, diet, birth mode, or stress may trigger or promote the translocation of intestinal microorganisms and microbial products (such as, LPS), which would cause oxidative stress and mucosal inflammation, and promote the accumulation of α-Syn in the enteric nervous system (ENS) (61-63). ...
Cognitive impairment (CI) is a common complication of Parkinson's disease (PD). The major features of Parkinson's disease with cognitive impairment (PD-CI) include convergence of α-Synuclein (α-Syn) and Alzheimer's disease (AD)-like pathologies, neuroinflammation, and dysbiosis of gut microbiota. Porphyromonas gingivalis ( P. gingivalis ) is an important pathogen in periodontitis. Recent research has suggested a role of P. gingivalis and its virulence factor in the pathogenesis of PD and AD, in particular concerning neuroinflammation and deposition of α-Synuclein (α-Syn) and amyloid-β (Aβ). Furthermore, in animal models, oral P. gingivalis could cause neurodegeneration through regulating the gut-brain axis, suggesting an oral-gut-brain axis might exist. In this article, we discussed the pathological characteristics of PD-CI and the role of P. gingivalis in them.
... In addition, it was shown dramatically in a mouse study published in 2019 that misfolded α-synuclein in the gut can be delivered to the brain via the vagus nerve to cause Parkinson's disease. A vagotomy completely protected the mice from transmission from the gut to the brain [22]. ...
... This gene could thus be linked to hypermetabolic states in SHRs, and was therefore categorized as Group-4. According to a previous reports, Snca is preferentially expressed on neuronal cells [27], where it may serve to integrate presynaptic signaling and membrane trafficking. However, its role in arteries is not known and therefore it was categorized in Group-3. ...
Background:
Although the mesenteric artery plays a key role in regulating peripheral blood pressure, the molecular mechanisms that underlie the development of essential hypertension are not yet fully understood.
Materials and methods:
We explored candidate genes for hypertension using three related strains of spontaneously hypertensive rats (SHRs) that mimic human essential hypertension. In this study we used DNA microarrays, a powerful tool for studying genetic diseases, to compare gene expression in the mesenteric artery of three SHR substrains: SHR, stroke-prone SHR (SHRSP), and malignant SHRSP (M-SHRSP).
Results:
Compared to normotensive 6-week old Wistar Kyoto rats (WKY), higher blood pressure correlated with overexpression of 31 genes and with down regulation of 24 genes. Adam23, which negatively regulates potassium current, and the potassium channel genes, Kcnc2 and Kcnq5, were associated with the onset of hypertension. In addition, Spock2 and Agtrap were identified as strengtheners of hypertension by analyzing up and down regulated genes at 9-weeks of age.
Conclusions:
Adam23, Kcnc2 and Kcnq5 appear to be factors for the onset of hypertension, while Spock2 and Agtrap are as factors that strengthen hypertension. These findings contribute to our understanding of the pathophysiology of hypertension and to the development of treatment for this condition.
... Parkinson's disease (PD) is known as a slowly progressive degenerative disease involving the peripheral and central nervous system (PNS and CNS), according to Braak's hypothesis (Braak and Del Tredici 2017). The full truncal vagotomy further proved that the misfolding α-synuclein (α-syn) could retrogradely spread from the gastrointestinal tract to the brain through vagal nerve, resulting in the loss of dopaminergic neurons in the substantia nigra (SN) and the decrease of dopamine in the striatum (Kim et al. 2019). Studies have shown that the motor symptoms didn't occur apparently until the PD patients lost 60-80% dopaminergic neurons in the SN (Deumens et al. 2002). ...
Gastrointestinal symptoms are common in the early-stage Parkinson's disease (PD), but its potential pathogenesis remains unclear. Therefore, in the present study, we used the 16S ribosomal RNA gene sequencing and gas chromatography coupled with mass spectrometry-based metabolomics to investigate the alterations of gut microbiome and serum amino acid levels in the early-stage PD mice model induced with rotenone. The results demonstrated that the microbial taxa at phylum, family and genus levels remarkably altered in rotenone-induced mice relative to vehicle-induced mice. The rotenone-induced mice had higher relative abundance of Flavobacteriaceae, Staphylococcaceae, and Prevotellaceae as well as lower relative abundance of Lachnospiraceae_UCG-001, Ruminiclostridium, and Prevotellaceae_NK3B31_group than vehicle-induced mice. The evaluation of serum amino acids revealed the alterations in several classes of amino acids, including L-proline, L-alanine, L-serine, L-asparagine, L-threonine, L-glutamine, L-methionine, and L-4-hydroxyproline. Notably, the altered serum amino acid levels were significantly associated with the abundance of gut microbiota, especially Ruminococcaceae and Ruminiclostridium. Our study explored the possible role of the gut-microbiota-metabolite axis in the early-stage PD and provided the possibility of prevention and treatment of PD by gut-microbiota-metabolite axis in the future.
... Evidence for: • Gut-to-brain α-synuclein transmission, accompanied by nigral dopaminergic neurodegeneration and PD-like motor and non-motor symptoms, has been demonstrated in rodent models 31,32 and is possibly age-dependent 33,34 . • In a rotenone mouse model of PD, hemivagotomy prevented both α-synuclein accumulation in the dorsal motor nucleus of the vagus nerve (DMNV) and nigral dopaminergic cell death ipsilateral to the procedure 12 . ...
Evidence for a close bidirectional link between the brain and the gut has led to a paradigm shift in neurology, especially in the case of Parkinson disease (PD), in which gastrointestinal dysfunction is a prominent feature. Over the past decade, numerous high-quality preclinical and clinical publications have shed light on the highly complex relationship between the gut and the brain in PD, providing potential for the development of new biomarkers and therapeutics. With the advent of high-throughput sequencing, the role of the gut microbiome has been specifically highlighted. Here, we provide a critical review of the literature on the microbiome-gut-brain axis in PD and present perspectives that will be useful for clinical practice. We begin with an overview of the gut-brain axis in PD, including the potential roles and interrelationships of the vagus nerve, α-synuclein in the enteric nervous system, altered intestinal permeability and inflammation, and gut microbes and their metabolic activities. The sections that follow synthesize the proposed roles of gut-related factors in the development and progression of, in responses to PD treatment, and as therapeutic targets. Finally, we summarize current knowledge gaps and challenges and delineate future directions for the field.
... Prions are self-propagating protein conformations, initially identified as infectious agents causing mammalian transmissible spongiform encephalopathies or prion diseases [1]. This prion concept of protein-based infectivity has now been implicated in several human amyloid-based diseases, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and type 2 (late-onset) diabetes [2][3][4][5]. Interestingly, multiple prion-forming proteins have been also discovered in Saccharomyces cerevisiae, which are transmitted as altered protein conformations that are linked to changes in phenotypes and thus referred to as yeast prions (see recent reviews of [6][7][8][9][10][11][12][13]). ...
(1) Background: Numerous prions exist in the budding yeast, including [SWI+], the prion form of Swi1-a subunit of the chromatin-remodeling complex SWI/SNF. Despite decades of research, the molecular mechanisms underlying prion initiation and propagation are not fully understood. In this study, we aimed to identify endogenous cellular proteins that destabilize [SWI+]. (2) Methods: We screened the MoBY-ORF 2.0 library for proteins that destabilize [SWI+] upon overproduction. We further explored the effects of the identified candidates against other yeast prions and analyzed their potential prion-curing mechanisms. (3) Results: Eighty-two [SWI+] suppressors were identified, and their effects were shown to be [SWI+]-specific. Interestingly, a few documented [SWI+] suppressors were not among the identified hits. Further experiments indicate that, for some of these [SWI+] suppressors, their overproduction, and thus their prion-curing activities, are regulated by environmental conditions. Bioinformatics analyses show that our identified [SWI+] suppressors are involved in diverse biological functions, with gene ontology term enrichments specifically for transcriptional regulation and translation. Competition for Swi1 monomers between [SWI+] and Swi1 interactors, including the SWI/SNF complex, is a potential prion-curing mechanism. (4) Conclusions: We identified a number of [SWI+]-specific suppressors that highlight unique features of [SWI+] in maintaining its self-perpetuating conformations.
... Another animal study published evidence that PD could begin in the gut, thereby validating Braak's hypothesis. This study injected exogenous pathological a-syn and observed its effect on the misfolding of endogenous synuclein and transmission through the vagus nerve (86). If a-syn accumulates in the gut, how does it connect the gut lumen and nervous system? ...
Recent epidemiological studies show a noticeable correlation between chronic microbial infections and neurological disorders. However, the underlying mechanisms are still not clear due to the biological complexity of multicellular and multiorgan interactions upon microbial infections. In this review, we show the infection leading to neurodegeneration mediated by multiorgan interconnections and neuroinflammation. Firstly, we highlight three inter-organ communications as possible routes from infection sites to the brain: nose-brain axis, lung-brain axis, and gut-brain axis. Next, we described the biological crosstalk between microglia and astrocytes upon pathogenic infection. Finally, our study indicates how neuroinflammation is a critical player in pathogen-mediated neurodegeneration. Taken together, we envision that antibiotics targeting neuro-pathogens could be a potential therapeutic strategy for neurodegeneration.
... Based on these data, they proposed a new hypothesis on the pathology of PD: alpha synuclein pathology typical for PD might spread from gut to brain presumable along the vagus nerve (Braak et al., 2003b). Later on indeed gut brain transmission of pathology with concomitant loss of dopaminergic neurons could be observed in mice after injection of prion-like alpha synuclein fibrils into gut muscles (Kim et al., 2019). While exogenous alpha synuclein could lead to mitochondrial disfunction, overexpression of parkin could rescue the mitochondrial disfunction (Wilkaniec et al., 2021). ...
The transcription factor NF-κB is commonly known to drive inflammation and cancer progression, but is also a crucial regulator of a broad range of cellular processes within the mammalian nervous system. In the present review, we provide an overview on the role of NF-κB in the nervous system particularly including its constitutive activity within cortical and hippocampal regions, neuroprotection as well as learning and memory. Our discussion further emphasizes the increasing role of human genetics in neurodegenerative disorders, namely, germline mutations leading to defects in NF-κB-signaling. In particular, we propose that loss of function mutations upstream of NF-κB such as ADAM17, SHARPIN, HOIL, or OTULIN affect NF-κB-activity in Alzheimer’s disease (AD) patients, in turn driving anatomical defects such as shrinkage of entorhinal cortex and the limbic system in early AD. Similarly, E3 type ubiquitin ligase PARKIN is positively involved in NF-κB signaling. PARKIN loss of function mutations are most frequently observed in Parkinson’s disease patients. In contrast to AD, relying on germline mutations of week alleles and a disease development over decades, somatic mutations affecting NF-κB activation are commonly observed in cells derived from glioblastoma multiforme (GBM), the most common malignant primary brain tumor. Here, our present review particularly sheds light on the mutual exclusion of either the deletion of NFKBIA or amplification of epidermal growth factor receptor (EGFR) in GBM, both resulting in constitutive NF-κB-activity driving tumorigenesis. We also discuss emerging roles of long non-coding RNAs such as HOTAIR in suppressing phosphorylation of IκBα in the context of GBM. In summary, the recent progress in the genetic analysis of patients, particularly those suffering from AD, harbors the potential to open up new vistas for research and therapy based on TNFα/NF-κB pathway and neuroprotection.
... As a result, there is an upregulation of α-synuclein expression and transport through the vagus nerve and into the brain. Increased permeability of the blood-brain barrier (BBB) facilitates the accumulation of α-synuclein within various brain regions, including the dorsal motor nucleus of the vagus nerve (DMV), leading to proinflammatory glial responses and the pathogenesis of neuroinflammation during PD being injected into the rat intestine where the translocation is supported by the microtubule-based axonal transport system [63][64][65]. In the brain, α-synuclein can trigger microglia activation, which is thought to be one of the most significant signatures of neuroinflammation. ...
Parkinson’s disease (PD) is the second most common neurodegenerative disorder which affects 6.1 million people worldwide. The neuropathological hallmarks include the loss of dopaminergic neurons in the substantia nigra, the presence of Lewy bodies and Lewy neurites caused by α-synuclein aggregation, and neuroinflammation in the brain. The prodromal phase happens years before the onset of PD during which time many patients show gastro-intestinal symptoms. These symptoms are in support of Braak’s theory and model where pathological α‐synuclein propagates from the gut to the brain. Importantly, immune responses play a determinant role in the pathogenesis of Parkinson’s disease. The innate immune responses triggered by microglia can cause neuronal death and disease progression. In addition, T cells infiltrate into the brains of PD patients and become involved in the adaptive immune responses. Interestingly, α‐synuclein is associated with both innate and adaptive immune responses by directly interacting with microglia and T cells. Here, we give a detailed review of the immunobiology of Parkinson’s disease, focusing on the role α-synuclein in the gut-brain axis hypothesis, the innate and adaptive immune responses involved in the disease, and current treatments.
... The apparatus was cleaned with 70% ethanol solution between each trial to avoid olfactory cues between animals. A video tracking system was used to record the total distance traveled as a measure of autonomous movement 55 . ...
The abnormal accumulation of α-synuclein (α-syn) is a crucial factor for the onset and pathogenesis of Parkinson’s disease (PD), and the autophagy-lysosome pathway (ALP) contributes to α-syn turnover. AMP-activated protein kinase (AMPK) and the mammalian target of rapamycin (mTOR) regulate autophagy by initiating the macroautophagy cascade and promoting lysosomal biogenesis via increased transcription factor EB (TFEB) activity. Hence, activation of AMPK-mTOR-TFEB axis-mediated autophagy might promote α-syn clearance in PD. Harmol is a β-carboline alkaloid that has been extensively studied in a variety of diseases but rarely in PD models. In this study, we aimed to evaluate the effect and underlying mechanism of harmol in PD models in vitro and in vivo. We show that harmol reduces α-syn via ALP in a dose- and time-dependent manner in cell model that overexpressed human A53T mutant α-syn. We also demonstrate that harmol promotes the translocation of TFEB into the nucleus and accompanies the restoration of autophagic flux and lysosomal biogenesis. Importantly, harmol improves motor impairment and down-regulates α-syn levels in the substantia nigra and prefrontal cortex in the α-syn transgenic mice model. Further studies revealed that harmol might activate ALP through AMPK-mTOR-TFEB to promote α-syn clearance. These in vitro and in vivo improvements demonstrate that harmol activates the AMPK-mTOR-TFEB mediated ALP pathway, resulting in reduced α-syn, and suggesting the potential benefit of harmol in the treatment of PD.
... Animal studies demonstrated that the intragastrically administered rotenone, a PD inducer, could cause pathological α-synuclein formation in ENS, in the vagal nerve, and then the brainstem. When vagotomy was performed, the pathological α-synuclein stopped transporting to the brain (Phillips et al., 2008;Kim et al., 2019). Furthermore, human α-synuclein injected into the intestinal wall of healthy mice could transport via the vagal nerve and reach the brainstem (Holmqvist et al., 2014). ...
An increasing number of studies have provided evidence for the hypothesis that the pathogenesis of Parkinson’s disease (PD) may derive from the gut. Firstly, Lewy pathology can be induced in the enteric nervous system (ENS) and be transported to the central nervous system (CNS) via the vagal nerve. Secondly, the altered composition of gut microbiota causes an imbalance between beneficial and deleterious microbial metabolites which interacts with the increased gut permeability and the gut inflammation as well as the systemic inflammation. The activated inflammatory status then affects the CNS and promotes the pathology of PD. Given the above-mentioned findings, researchers start to pay attention to the connection between PD and gastrointestinal diseases including irritable bowel syndrome, inflammatory bowel disease (IBD), microscopic colitis (MC), gastrointestinal infections, gastrointestinal neoplasms, and colonic diverticular disease (CDD). This review focuses on the association between PD and gastrointestinal diseases as well as the pathogenesis of PD from the gut.
... The theory postulates that external stressors stimulate an immune response in the gut, which triggers and seeds pathology from the enteric system to the brain via the vagal nerve 33 . In support of this, evidence suggests that pathological (or misfolded) aSyn inoculated into the duodenum can spread from the gut into the brain of rodents 36 and that severing the vagal nerve inhibits this phenomenon 37 . Furthermore, oral administration of the pesticide rotenone triggers synucleinopathy, which spreads from the GI into the brain of inoculated mice 34 . ...
Parkinson’s Disease (PD) is a neurodegenerative disorder characterized, in part, by the loss of dopaminergic neurons within the nigral-striatal pathway. Multiple lines of evidence support a role for reactive nitrogen species (RNS) in degeneration of this pathway, specifically nitric oxide (NO). This review will focus on how RNS leads to loss of dopaminergic neurons in PD and whether RNS accumulation represents a central signal in the degenerative cascade. Herein, we provide an overview of how RNS accumulates in PD by considering the various cellular sources of RNS including nNOS, iNOS, nitrate, and nitrite reduction and describe evidence that these sources are upregulating RNS in PD. We document that over 1/3 of the proteins that deposit in Lewy Bodies, are post-translationally modified (S-nitrosylated) by RNS and provide a broad description of how this elicits deleterious effects in neurons. In doing so, we identify specific proteins that are modified by RNS in neurons which are implicated in PD pathogenesis, with an emphasis on exacerbation of synucleinopathy. How nitration of alpha-synuclein (aSyn) leads to aSyn misfolding and toxicity in PD models is outlined. Furthermore, we delineate how RNS modulates known PD-related phenotypes including axo-dendritic-, mitochondrial-, and dopamine-dysfunctions. Finally, we discuss successful outcomes of therapeutics that target S-nitrosylation of proteins in Parkinson’s Disease related clinical trials. In conclusion, we argue that targeting RNS may be of therapeutic benefit for people in early clinical stages of PD.
... In Parkinson's Disease (PD), the role of the gut-brain axis has been greatly highlighted by recent developments in both clinical and preclinical research [1][2][3][4][5] . ...
In Parkinson’s Disease (PD), recent evidence points toward the involvement of the gut-brain axis as one of the primary physio pathological mechanisms underlying α-Synuclein aggregation and propagation to CNS. Furthermore, gastrointestinal dysfunctions represent one of the main non-motor symptoms in PD, often preceding the development of proper motor symptoms. We aimed to investigate the enteric nervous system (ENS) in PD by characterizing α-Syn alterations and glial responses in duodenum biopsies of PD patients.
Patients with symptomatic PD which underwent Duodopa Percutaneous Endoscopic Gastrostomy and Jejunal Tube (PEG-J) procedure were included in the study. A mean of 4 wall biopsies were sampled from each patient. Immunohistochemistry was performed with anti-aggregated α-Syn (5G4) and GFAP antibodies. Morphometrical-semi-quantitative analysis was performed to characterize 5G4+ and GFAP+ density and size. Duodenal control biopsies were included from age- and-sex-matched patients undergoing routine diagnostic endoscopy.
Elevated immunoreactivity for aggregated α-Syn was identified in all biopsies of PD patients compared to controls. 5G4+ partially colocalized with neuronal marker β-III-tubulin but was found also outside enteric neurons. Evaluation of enteric glia cells revealed an increased size and density when compared with controls suggesting reactive gliosis.
The ENS could be one of the earliest implicated structures in the pathophysiology of PD. The analysis of enteric glia could represent a precocious biological marker of the disease, as its responses to pathological α-Syn could unveil a link between gastrointestinal neural and immune systems in PD inflammation.
Background
Perioperative neurocognitive disorders (PND) is a common postoperative disease in elderly patients, but its pathogenesis remains unclear.
Methods
Exploratory laparotomy was performed to establish PND model under sevoflurane anesthesia. 16S rRNA high-throughput sequencing was used to detect the changes of intestinal flora. Antibiotics were used to relatively eliminate intestinal flora before anesthesia/surgery, and behavior tests, such as open field, Y maze, and fear conditioning tests were applied to detect the changes of memory ability. The number of Th17 cells and Foxp3 cells was detected by flow cytometry in the Peyer's patches (PP), mesenteric lymph nodes (MLN), blood and brain. Western blot was used to detect the expression of IL17, IL17RA, IL6 and IL10 in the hippocampus. Immunofluorescence was used to detect the expression of IL17, IL17R and IBA1 (ionized calcium binding adaptor molecule1) in the hippocampus.
Results
Anesthesia/surgery caused intestinal flora imbalance and induced neurocognitive impairment, increased the number of Th17 cells in the PP, MLN, blood and brain, increased the level of IL17, IL17R and inflammatory factors production in the hippocampus. Antibiotics administration before anesthesia/surgery significantly decreased the number of Th17 cells and the level of IL17, IL17R and inflammatory factors production, and improved the memory function. In addition, we found that IL17R was co-labeled with IBA1 in a large amount in the hippocampus through immunofluorescence double-staining.
Conclusion
Our study suggested that intestinal dysbacteriosis-propelled T helper 17 cells activation and IL17 secretion might play an important role in the pathogenesis of PND induced by anesthesia/surgery in aged rats.
Objectives:
It has long been considered that accumulation of pathological alpha-synuclein (aSyn) leads to synaptic/neuronal loss which then results in behavioural and cognitive dysfunction. To investigate this claim, we investigated effects downstream of aSyn preformed fibrils (PFF) and 6-hydroxydopamine (6-OHDA), because aSyn PFFs induce spreading/accumulation of aSyn, and 6-OHDA rapidly causes local neuronal loss.
Materials and methods:
We injected mouse aSyn PFFs into the medial forebrain bundle (MFB) of Sprague-Dawley rats. We investigated spread of pathological aSyn, phosphorylation of aSyn and tau, oxidative stress, synaptic/neuronal loss, and cognitive dysfunction 60, 90 and 120 days after injection. Similarly, we injected 6-OHDA into the MFB and examined the same parameters 1 and 3 weeks after injection.
Results:
Following aSyn PFF injection, phosphorylated aSyn was found distant from the injection site in the hippocampus and frontal cortex. However, despite neuron loss being evident close to the site of injection in the substantia nigra at 120 days post injection, there were no other neurodegeneration-associated features associated with aSyn including synaptic loss. In contrast, 6-OHDA caused severe neuronal loss in the substantia nigra at 3 weeks post injection that was accompanied by phosphorylation of aSyn and tau, oxidative stress, loss of synaptic proteins, cognitive and motor dysfunction.
Conclusions:
Our results demonstrate that spread/replication and slow accumulation of pathological aSyn may not be sufficient to induce neurodegenerative changes. In contrast, oxidative stress responses in addition to aSyn accumulation were associated with other PD-associated abnormalities and cognitive dysfunction. Our results may be important when considering why only some Parkinson's disease patients develop dementia.
Purpose of Review
Neuroinflammation plays a significant role in Parkinson’s disease (PD) etiology along with mitochondrial dysfunction and impaired proteostasis. In this context, mechanisms related to immune response can act as modifiers at different steps of the neurodegenerative process and justify the growing interest in anti-inflammatory agents as potential disease-modifying treatments in PD. The discovery of inherited gene mutations in PD has allowed researchers to develop cellular and animal models to study the mechanisms of the underlying biology, but the original cause of neuroinflammation in PD is still debated to date.
Recent Findings
Cell autonomous alterations in neuronal cells, including mitochondrial damage and protein aggregation, could play a role, but recent findings also highlighted the importance of intercellular communication at both local and systemic level. This has given rise to debate about the role of non-neuronal cells in PD and reignited intense research into the gut-brain axis and other non-neuronal interactions in the development of the disease. Whatever the original trigger of neuroinflammation in PD, what appears quite clear is that the aberrant activation of glial cells and other components of the immune system creates a vicious circle in which neurodegeneration and neuroinflammation nourish each other.
Summary
In this review, we will provide an up-to-date summary of the main cellular alterations underlying neuroinflammation in PD, including those induced by environmental factors (e.g. the gut microbiome) and those related to the genetic background of affected patients. Starting from the lesson provided by familial forms of PD, we will discuss pathophysiological mechanisms linked to inflammation that could also play a role in idiopathic forms. Finally, we will comment on the potential clinical translatability of immunobiomarkers identified in PD patient cohorts and provide an update on current therapeutic strategies aimed at overcoming or preventing inflammation in PD.
An in vitro platform was designed and optimized for the co-culture of probiotic anaerobic bacteria with a primary human colonic epithelium having a goal of assessing the anti-inflammatory impact of the probiotic bacteria. The device maintained a luminal O2 concentration at <1% while also supporting an oxygenated basal compartment at 10% for at least 72 h. Measurement of the transepithelial resistance of a confluent colonic epithelium showed high monolayer integrity while fluorescence assays demonstrated that the monolayer was comprised primarily of goblet cells and colonocytes, the two major differentiated cell subtypes of the colonic epithelium. High monolayer barrier function and viability were maintained during co-culture of the epithelium with the probiotic obligate anaerobe Anaerobutyricum hallii (A. hallii). Importantly the device supported a static co-culture of microbes and colonic epithelium mimicking the largely static or low flow conditions within the colonic lumen. A model inflamed colonic epithelium was generated by the addition of tumor necrosis factor-α (TNF-α) and lipopolysaccharide (LPS) to the basal and luminal epithelium sides, respectively. Co-culture of A. hallii with the LPS/TNF-α treated intestine diminished IL-8 secretion by ≥40% which could be mimicked by co-culture with the A. hallii metabolite butyrate. In contrast, co-culture of the inflamed epithelium with two strains of lactic acid-producing bacteria, Lactobacillus rhamnosus GG (LGG) and Bifidobacterium adolescentis (B. adolescentis), did not diminish epithelial IL-8 secretion. Co-culture with colonic epithelial cells from different donors demonstrated a consistent anti-inflammatory effect by A. hallii, but distinct responses to co-culture with LGG and B. adolescentis. The demonstrated system offers a simple and easily adopted platform for examining the physiologic impact of alterations in the intestinal epithelium that occur in the presence of probiotic bacteria and their metabolites.
La maladie de Parkinson (MP) est une pathologie neurodégénérative caractérisée par la perte progressive des neurones dopaminergiques de la substantia nigra pars compacta (SNc). Malgré une avancée considérable des traitements proposés aux patients, la MP reste à ce jour toujours incurable. Les deux principaux facteurs qui expliquent cet échec thérapeutique sont : i) une compréhension incomplète de la physiopathologie de la MP, et ii) son diagnostic tardif.En effet, celui-ci est basé sur l’évaluation de symptômes moteurs caractéristiques de la maladie qui apparaissent alors que le processus neurodégénératif est déjà très avancé (50-60% des neurones de la SNc sont déjà morts). Pourtant, il a été montré que les patients atteints de la MP peuvent également présenter des troubles neuropsychiatriques qui apparaissent avant les symptômes moteurs et même dès les phases précoces de la maladie.De manière intéressante, des altérations du métabolisme cérébral, mais également du métabolisme sanguin, ont été identifiées chez des patients atteints de la MP, et chez des patients présentant des symptômes neuropsychiatriques semblables à ceux observés chez les patients parkinsoniens. A ce jour, aucune étude métabolique ne s’est intéressée spécifiquement aux troubles neuropsychiatriques et à la MP de façon conjointe. La comparaison du profil métabolique à différents stades de la pathologie, et notamment dès les phases précoces, pourrait non seulement servir d’outil diagnostic, mais également permettre d’identifier des cibles pertinentes pour le développement de stratégies thérapeutiques.Dans ce contexte, l’objectif de ma thèse a été d’étudier les altérations du métabolisme associées aux différentes phases de la maladie, et notamment aux phases précoces. L’originalité de cette étude repose sur l’utilisation d’échantillons provenant de plusieurs modèles animaux mais également de patients. Ainsi, nous avons conduit des études de métabolomique par résonance magnétique nucléaire (RMN) sur des échantillons de sérum provenant des modèles de rat 6-OHDA, rat alpha-synucléine et de primate non-humain MPTP, mimant différents stades de la maladie, ainsi qu’à partir d’échantillons sanguins provenant de 3 cohortes de patients nouvellement diagnostiqués.La comparaison des dérégulations métaboliques observées chez l’animal et chez l’humain dans le sérum nous a permis de développer un biomarqueur capable de séparer les patients nouvellement diagnostiqués des contrôles avec une grande fiabilité. De même, nous avons montré que notre biomarqueur permettait de clairement séparer les animaux mimant les phases précoces des animaux mimant les phases plus tardives, suggérant ainsi qu’il pourrait être utilisé pour un diagnostic très précoce de la MP.Des dérégulations communes au niveau sanguin et cérébral nous ont permis d’émettre des hypothèses mécanistiques quant à la physiopathologie de la MP.Notamment, des altérations associées au métabolisme du pyruvate ont particulièrement retenu notre attention, compte tenu de son implication dans le métabolisme énergétique qui est fortement impacté dans la maladie. Celles-ci nous ont conduit à formuler l’hypothèse que le pyruvate ne serait plus utilisé comme source énergétique préférentielle au sein de la cellule, possiblement à cause d’un blocage au niveau de l’entrée dans la mitochondrie. Pour tester cette hypothèse, nous avons bloqué chez des rats normaux le transporteur mitochondrial du pyruvate (MPC), qui est le seul point d'entrée du pyruvate dans la matrice mitochondriale et joue un rôle crucial dans le métabolisme énergétique. Ainsi, nous avons pu mettre en évidence que le blocage du MPC entraîne une redirection de la production d'énergie cellulaire au profit d’autres sources comme les lipides et les acides aminés. Cette redirection s’accompagnait d’une atténuation des atteintes cellulaire et comportementale chez le rat 6-OHDA, mettant ainsi en lumière les capacités neuroprotectrices du blocage du MPC pour la MP.
Inflammation has increasingly become a focus of study in regards to Parkinson’s disease (PD). Moreover, both central and peripheral sources of inflammation have been implicated in the pathogenesis of PD. Central inflammation consisting of activated microglia, astroglia, and T cell responses within the PD central nervous system; and peripheral inflammation referring to activated innate cells and T cell signaling in the enteric nervous system, gastrointestinal tract, and blood. This review will highlight important work that further implicates central and peripheral inflammation in playing a role in PD. We also discuss how these two distant inflammations appear related and how that may be mediated by autoantigenic responses to α-syn.
Controversial information about the role of chaperonins in the amyloid transformation of proteins and, in particular, α-synuclein, requires a more detailed study of the observed effects due to the structure and functional state of various chaperonins. In this work, two types of phage chaperonins, the double-ring EL and the single-ring OBP, were shown to stimulate α-synuclein fibrillation in an ATP-dependent manner. Chaperonin morphology does not affect the stimulation of α-synuclein amyloid transformation. However, the ATP-dependent effect of single- and double-ring chaperonins on this process differs, which can lead to different morphology of resulting fibrils. Fibril formation seems to proceed without substrate encapsulation in the internal cavity of chaperonin, because of the structural features of phage chaperonins and their ability to function without co-chaperonins. In the absence of ATP, both chaperonins, on the contrary, completely prevent α-synuclein amyloid transformation, which provides the possibility of their use as anti-amyloid agents, in the form of incomplete molecules or mutants with suppressed ATPase activity.
There are currently no treatments to delay or prevent Parkinson's disease (PD), and protective treatments require early administration. Targeting axonal degeneration in early PD could have an important clinical effect; however, the underlying molecular mechanisms controlling axonal degeneration in PD are not fully understood. Here, we studied the role of Wnt/β-catenin signaling in axonal degeneration induced by 6-hydroxydopamine (6-OHDA) or overexpression of alpha-synuclein (α-Syn) in vitro and in vivo. We found that the levels of both β-catenin and p-S9-glycogen synthase kinase-3β (GSK-3β) increased and the levels of phosphorylated β-catenin (p-β-catenin) decreased during 6-OHDA-induced axonal degeneration and that the inhibitors of the Wnt/β-catenin pathway IWR-1 and Dickkopf-1 (DKK-1) attenuated the degenerative process in primary neurons in vitro. Furthermore, IWR-1 enhanced the increase of LC3-II levels and the decrease of p62 triggered by 6-OHDA treatment, whereas the autophagy inhibitor 3-Methyladenine (3-MA) alleviated the protective effect of IWR-1 on axons in vitro. Consistent with the in vitro findings, both β-catenin and p-S9-GSK-3β were upregulated in a 6-OHDA-induced rat PD model, and blocking the Wnt/β-catenin pathway with DKK-1 attenuated the degeneration of dopaminergic axons at an early time point in vivo. The protective effect of inhibition of Wnt/β-catenin signaling was further confirmed in an α-Syn overexpression-induced animal models of PD. Taken together, these data indicate that the Wnt/β-catenin pathway is involved axonal degeneration in PD, and suggest that Wnt/β-catenin pathway inhibitors have the therapeutic potential for the prevention of PD.
In the last decade, it has become increasingly recognized that a balanced gut microbiota plays an important role in maintaining the health of the host. Numerous clinical and preclinical studies have shown that changes in gut microbiota composition are associated with a variety of neurological diseases, eg, Parkinson's disease, Alzheimer's disease, and myasthenia gravis. However, the underlying molecular mechanisms are complex and remain unclear. Behavioral phenotypes can be transmitted from humans to animals through gut microbiota transplantation, indicating that the gut microbiota may be an important regulator of neurological diseases. However, further research is required to determine whether animal-based findings can be extended to humans and to elucidate the relevant potential mechanisms by which the gut microbiota regulates neurological diseases. Such investigations may aid in the development of new microbiota-based strategies for diagnosis and treatment and improve the clinical management of neurological disorders. In this review, we describe the dysbiosis of gut microbiota and the corresponding mechanisms in common neurological diseases and discuss the potential roles that the intestinal microbiome may play in the diagnosis and treatment of neurological disorders.
Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease, with typical motor symptoms as the main clinical manifestations. At present, there are about 10 million patients with PD in the world, and its comorbidities and complications are numerous and incurable. Therefore, it is particularly important to explore the pathogenesis of PD and find possible therapeutic targets. Because the etiology of PD is complex, involving genes, environment, and aging, finding common factors is the key to identifying intervention targets. Hypoxia is ubiquitous in the natural environment and disease states, and it is considered to be closely related to the etiology of PD. Despite research showing that hypoxia increases the expression and aggregation of alpha-synuclein (α-syn), the most important pathogenic protein, there is still a lack of systematic studies on the role of hypoxia in α-syn pathology and PD pathogenesis. Considering that hypoxia is inextricably linked with various causes of PD, hypoxia may be a co-participant in many aspects of the PD pathologic process. In this review, we describe the risk factors for PD, and we discuss the possible role of hypoxia in inducing PD pathology by these risk factors. Furthermore, we attribute the pathological changes caused by PD etiology to oxygen uptake disorder and oxygen utilization disorder, thus emphasizing the possibility of hypoxia as a critical link in initiating or promoting α-syn pathology and PD pathogenesis. Our study provides novel insight for exploring the pathogenesis and therapeutic targets of PD.
Age‐related central neurodegenerative diseases, such as Alzheimer’s and Parkinson’s disease, are a rising public health concern and have been plagued by repeated drug development failures. The complex nature and poor mechanistic understanding of the etiology of neurodegenerative diseases has hindered the discovery and development of effective disease‐modifying therapeutics. Quantitative systems pharmacology models of neurodegeneration diseases may be useful tools to enhance the understanding of pharmacological intervention strategies and to reduce drug attrition rates. Due to the similarities in pathophysiological mechanisms across neurodegenerative diseases, especially at the cellular and molecular level, we envision the possibility of structural components that are conserved across models of neurodegenerative diseases. Conserved structural submodels can be viewed as building blocks that are pieced together alongside unique disease components to construct QSP models of neurodegenerative diseases. Model parameterization would likely be different between the different types of neurodegenerative diseases as well as individual patients. Formulating our mechanistic understanding of neurodegenerative pathophysiology as a mathematical model could aid in the identification and prioritization of drug targets and combinatorial treatment strategies, evaluate the role of patient characteristics on disease progression and therapeutic response, and serve as a central repository of knowledge. Here we provide a background on neurodegenerative diseases, highlight hallmarks of neurodegeneration, and summarize previous quantitative systems pharmacology models of neurodegenerative diseases.
Background:
Pathological changes in the brain can affect the gastrointestinal tract, whereas there is less evidence regarding the brain-gut axis.
Objective:
To identify whether cerebral endogenous phosphorylated α-synuclein induces gastrointestinal dysfunction via the brain-gut axis, mediated by the vagus nerve.
Methods:
α-syn N103/tau N368 preformed fibrils were injected into the dorsal lateral striatum of rodents, and the cerebral and colonic synucleinopathies and changes in the enteric nervous system were analyzed. Moreover, subdiaphragmatic vagotomy was conducted to confirm the role of the vagus nerve in brain-gut propagation.
Results:
An anterograde propagation of phosphorylated α-synuclein from the brain to the proximal colon mainly via the vagus nerve was observed at one month. The accumulation of phosphorylated α-synuclein was detected in the proximal colon over time, accompanied by infiltration of macrophages and eosinophils in the mucosa and submucosa. Upon injection with lower doses of preformed fibrils, the accumulation of phosphorylated α-synuclein and dopaminergic neuron loss was reduced to levels consistent with control at six months, while the expression levels of GFAP, Iba-1, and IL-6 increased. Under high preformed fibrils dose conditions, fecal traits and gastrointestinal motility were significantly reduced at six months, and aggregations of phosphorylated α-synuclein and an increasing level of IL-1β appeared.
Conclusion:
Induced endogenous α-synuclein can quickly propagate into the proximal colon mainly via the vagus nerve. Injections of low doses of preformed fibrils can elicit recovery of the enteric nervous system and degradation of α-synuclein aggregates whereas high doses cause accumulation of pathological α-synuclein, enteric inflammation, and prominent gastrointestinal dysfunction.
Background
: Parkinson's disease (PD) is a progressive neurodegenerative disease, which brings increasing threaten for human healthy and is still lacking of satisfied treatment. Recently, numerous studies have also demonstrated the effect of particular subsets of CD4+ T cells on PD pathology. Th17 cells played an important role in the pathogenesis of PD. Traditional Chinese medicine has been widely used to treat PD clinically, and has a tremendous potential in clinical drug development.
Purpose
: The aim of this study was to verify the therapeutic effects of DHY. on PD mice model, and investigate the underlying molecular mechanism.
Methods
: Herein, we verified the effect of a traditional Chinese medicine formula, named DiHuangYin (DHY), on the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced mouse model of PD through behavioral and histopathological tests. High-resolution mass spectrometry combined with molecular networking were applied for substance profiling of DHY. Based on the chemical composition of DHY, network pharmacology was performed. Flow cytometry and ELISA were used to evaluate the expressions of cytokines in peripheral immune system. qPCR and immunofluorescence were used to detect the inflammation infiltration of central nervous system.
Results
: DHY improves the motor function and prevents the loss of dopaminergic neurons in the MPTP induced mouse model of PD. 120 components of DHY were identified or tentatively characterized based on the MS/MS data and molecular networking. Network pharmacology suggested IL-17 signaling pathway and neuroactive ligand-receptor interaction as the important targets. Compared to the MPTP-intoxicated mice, the DHY group showed a decreased number of Th17 cells from splenocytes and a decreased level of IL-17A in the serum. On the other hand, less inflammatory infiltration was found in the midbrain of DHY treatment mice which might be associated with the attenuated peripheral inflammation.
Conclusions
: Though the underlying pharmacological mechanism of DHY is still lacking, we provided evidence that DHY decoction could protect dopaminergic neurons by mitigating peripheral inflammation.
Parkinson’s disease (PD) is the second-most common neurodegenerative disorder characterized by several motor and nonmotor symptoms. Lewy body inclusions containing aggregates of a presynaptic protein α-synuclein (αSyn) inside the central nervous system hallmarks PD pathophysiology. Multiple other sites in the peripheral nervous system and the enteric nervous system have shown to be infested by αSyn pathological aggregates. Emerging studies have found correlations of the microbiota-gut-brain axis and αSyn pathology in PD as a critical determinant for the onset of nonmotor symptoms, including gastrointestinal dysfunction, autonomic dysregulation, psychosis, sleep disturbances, and mood disorders. In the present chapter, we provide a comprehensive review on the role of the microbiome and its intertwined relationships with αSyn pathology that might play crucial role(s) in the initiation and progression of PD.
Alterations in gastrointestinal (GI) function and the gut‐brain axis are associated with progression and pathology of Alzheimer's Disease (AD). Studies in AD animal models show that changes in the gut microbiome and inflammatory markers can contribute to AD development in the central nervous system (CNS). Amyloid‐beta (Aβ) accumulation is a major AD pathology causing synaptic dysfunction and neuronal death. Current knowledge of the pathophysiology of AD in enteric neurons is limited, and whether Aβ accumulation directly disrupts enteric neuron function is unknown. In 6‐month‐old 5xFAD (transgenic AD) and wildtype (WT) male and female mice, GI function was assessed by colonic transit in vivo; propulsive motility and GI smooth muscle contractions ex vivo; electrochemical detection of enteric nitric oxide release in vitro, and changes in myenteric neuromuscular transmission using smooth muscle intracellular recordings. Expression of Aβ in the brain and colonic myenteric plexus in these mice was determined by immunohistochemistry staining and ELISA assay. At 6 months, 5xFAD mice did not show significant changes in GI motility or synaptic neurotransmission in the small intestine or colon. 5xFAD mice, but not WT mice, showed abundant Aβ accumulation in the brain. Aβ accumulation was undetectable in the colonic myenteric plexus of 5xFAD mice. 5xFAD AD mice are not a robust model to study amyloidosis in the gut as these mice do not mimic myenteric neuronal dysfunction in AD patients with GI dysmotility. An AD animal model with enteric amyloidosis is required for further study. Amyloidosis in central and enteric nervous system contribute to congenic impairment and gastrointestinal dysmotility in Alzheimer's Disease (AD). 5xFAD mice, a transgenic mouse model of AD, mimic the amyloidosis in central nervous system but lacking amyloidosis in enteric nervous system.
Genetic component of Parkinson's disease, once firmly believed non-existent, involves the human genome, mitochondrial genome, and the microbiome. Understanding the genomics of PD requires identification of PD-relevant genes and learning how they interact within the hologenome and with their environment. This chapter is an evidence-based perspective of a geneticist on how far we have come in this endeavor. The contemporary scientific society started with a naive and simplistic view of PD, evolved to accept that Parkinson's disease is probably the most complex disease there is, the progress we have made in discovering the genes and elucidating their functions, and now assembling the parts to create the whole.
Background:
The pathology underlying cognitive changes in people with Parkinson's disease (PD) is not well understood. In healthy older adults, gut microbiome composition has been associated with cognitive function. In people with PD, preliminary evidence suggests that cortical spreading of abnormal alpha-synuclein aggregates may be associated with cognitive impairment. As changes in the gut have been linked to PD onset and associated Lewy body pathology, an investigation of the gut microbiome and cognition in PD is warranted.
Objective:
To synthesise existing evidence on the relationship between the gut microbiome and cognitive function in PD.
Methods:
A systematic review was conducted to search for peer-reviewed articles and grey literature published to July 2021 across seven electronic databases (MEDLINE, EMBASE, PsycINFO, Scopus, Cochrane Library, ProQuest, and ProQuest Dissertations and Theses). English language articles reporting the relationship between cognition and the gut microbiome in human participants with PD were considered for inclusion. Results were qualitatively synthesised and evidence quality was assessed using the QualSyst tool for quantitative studies.
Results:
Five cross-sectional studies reporting the association between the gut microbiome and cognition in 395 participants with PD were included. Studies provided preliminary evidence of a relationship between cognition and gut microbiota within the Bacteroidetes and Firmicutes phyla, however, associations with specific genera were inconsistent across studies.
Conclusions:
Some species of short-chain fatty acid-producing bacteria (e.g. acetate, butyrate, and propionate producers) appear to be reduced in participants with PD with cognitive impairment. More research with larger samples and more consistent methodology is needed to substantiate these findings.
Zusammenfassung
Neueste wissenschaftlichen Erkenntnisse über das vegetative Nervensystem werfen unser Denkmodell der Anatomie über den Haufen. Aktuelle Studien zeigen, dass es anscheinend keine parasympathischen Nervenfasern im sakralen Rückenmark gibt. Zudem zählen, neben Sympathikus und Parasympathikus, noch zwei weitere Strukturen zum vegetativen Nervensystem – das enterische Nervensystem und das „little brain on the heart“.
Die klinischen Krankheitsbilder der vegetativen Nervensysteme sind längst Gegenstand der osteopathischen Forschung und lassen sich anscheinend positiv beeinflussen.
With its capacity to modulate motor control and motivational as well as cognitive functions dopamine is implicated in numerous neuropsychiatric diseases. The present study investigated whether an imbalance in dopamine homeostasis as evident in the dopamine overexpressing rat model (DAT-tg), results in learning and memory deficits associated with changes in adult hippocampal neurogenesis. Adult DAT-tg and control rats were subjected to the Morris water maze, the radial arm maze and a discrimination reversal paradigm and newly generated neurons in hippocampal circuitry were investigated post mortem. DAT-tg rats were found to exhibit a striking inability to acquire information and deploy spatial search strategies. At the same time, reduced integration of adult-born neurons in hippocampal circuitry was observed, which together with changes in striatal dopamine signalling might explain behavioural deficits.
Background:
Intraneuronal α-synuclein (α-Syn) aggregates known as Lewy bodies (LBs) and the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) are the pathological hallmarks of Parkinson's disease (PD). Braak's hypothesis based on autopsy studies suggests that Lewy pathology initially occurs in the enteric nervous system (ENS) and then travels retrogradely to the dorsal motor nucleus of the vagus nerve (dmX), proceeding from there in a caudo-rostral direction. Recent evidence that α-Syn aggregates propagate between interconnected neurons supports this hypothesis. However, there is no direct evidence demonstrating this transmission from the ENS to the dmX and then to the SNpc.
Methods:
We inoculated α-Syn preformed fibrils (PFFs) or phosphate-buffered saline (PBS) into the mouse gastric wall and analyzed the progression of the pathology.
Results:
The mice inoculated with α-Syn PFFs, but not with PBS, developed phosphorylated α-Syn (p-α-Syn)-positive LB-like aggregates in the dmX at 45 days postinoculation. This aggregate formation was completely abolished when vagotomy was performed prior to inoculation of α-Syn PFFs, suggesting that the aggregates in the dmX were retrogradely induced via the vagus nerve. Unexpectedly, the number of neurons containing p-α-Syn-positive aggregates in the dmX decreased over time, and no further caudo-rostral propagation beyond the dmX was observed up to 12 months postinoculation. P-α-Syn-positive aggregates were also present in the myenteric plexus at 12 months postinoculation. However, unlike in patients with PD, there was no cell-type specificity in neurons containing those aggregates in this model.
Conclusions:
These results indicate that α-Syn PFF inoculation into the mouse gastrointestinal tract can induce α-Syn pathology resembling that of very early PD, but other factors are apparently required if further progression of PD pathology is to be replicated in this animal model.
Accumulating evidence suggests that certain gut microbiota have antidepressant-like behavioural effects and that the microbiota can regulate neurogenesis and the expression of brain-derived neurotrophic factor (BDNF) in the hippocampus. The precise mechanisms underlying these effects are not yet clear. However, the vagus nerve is one of the primary bidirectional routes of communication between the gut and the brain and thus may represent a candidate mechanism. Yet, relatively little is known about the direct influence of vagus nerve activity on hippocampal function and plasticity. Thus, the aim of the present study was to determine whether constitutive vagus nerve activity contributes to the regulation of neurogenesis and BDNF mRNA expression in the hippocampus. To this end, we examined the impact of subdiaphragmatic vagotomy in adult mice on these parameters. We found that vagotomy decreased BDNF mRNA in all areas of the hippocampus. Vagotomy also reduced the proliferation and survival of newly born cells and decreased the number of immature neurons, particularly those with a more complex dendritic morphology. Taken together, these findings suggest that vagal nerve activity influences neurogenesis and BDNF mRNA expression in the adult hippocampus.
Changes in resident microbiota may have wide-ranging effects on human health. We investigated whether early life microbial disruption alters neurodevelopment and behavior in larval zebrafish. Conventionally colonized, axenic, and axenic larvae colonized at 1 day post fertilization (dpf) were evaluated using a standard locomotor assay. At 10 dpf, axenic zebrafish exhibited hyperactivity compared to conventionalized and conventionally colonized controls. Impairment of host colonization using antibiotics also caused hyperactivity in conventionally colonized larvae. To determine whether there is a developmental requirement for microbial colonization, axenic embryos were serially colonized on 1, 3, 6, or 9 dpf and evaluated on 10 dpf. Normal activity levels were observed in axenic larvae colonized on 1–6 dpf, but not on 9 dpf. Colonization of axenic embryos at 1 dpf with individual bacterial species Aeromonas veronii or Vibrio cholerae was sufficient to block locomotor hyperactivity at 10 dpf. Exposure to heat-killed bacteria or microbe-associated molecular patterns pam3CSK4 or Poly(I:C) was not sufficient to block hyperactivity in axenic larvae. These data show that microbial colonization during early life is required for normal neurobehavioral development and support the concept that antibiotics and other environmental chemicals may exert neurobehavioral effects via disruption of host-associated microbial communities.
Background:
Gastrointestinal symptoms are early events in Parkinson's disease (PD). The gastrointestinal hormone ghrelin was neuroprotective in the nigrostriatal dopamine system. The objective of this study was to assess ghrelin levels in the early stages of PD.
Methods:
Plasma was collected in the fasting state in 291 PD patients in stages 1-3 and 303 age- and sex-matched healthy controls. Additional samples were taken in the glucose response test to assess nutrition-related ghrelin levels in 20 PD patients and 20 healthy controls. The enzyme-linked immunosorbent assay was used to measure total and active plasma ghrelin levels.
Results:
We reported that total and active plasma ghrelin levels were decreased in PD, although there was no difference across progressive PD stages. Postprandial ghrelin suppression and preprandial peak responses were both attenuated in PD.
Conclusions:
Plasma ghrelin levels were decreased in PD; however, this event might be irrelevant to PD progression. Ghrelin responses to meals were also impaired in PD. © 2017 International Parkinson and Movement Disorder Society.
Objective:
To examine whether vagotomy decreases the risk of Parkinson disease (PD).
Methods:
Using data from nationwide Swedish registers, we conducted a matched-cohort study of 9,430 vagotomized patients (3,445 truncal and 5,978 selective) identified between 1970 and 2010 and 377,200 reference individuals from the general population individually matched to vagotomized patients by sex and year of birth with a 40:1 ratio. Participants were followed up from the date of vagotomy until PD diagnosis, death, emigration out of Sweden, or December 31, 2010, whichever occurred first. Vagotomy and PD were identified from the Swedish Patient Register. We estimated hazard ratios (HRs) with 95% confidence intervals (CIs) using Cox models stratified by matching variables, adjusting for country of birth, chronic obstructive pulmonary disease, diabetes mellitus, vascular diseases, rheumatologic disease, osteoarthritis, and comorbidity index.
Results:
A total of 4,930 cases of incident PD were identified during 7.3 million person-years of follow-up. PD incidence (per 100,000 person-years) was 61.8 among vagotomized patients (80.4 for truncal and 55.1 for selective) and 67.5 among reference individuals. Overall, vagotomy was not associated with PD risk (HR 0.96, 95% CI 0.78-1.17). However, there was a suggestion of lower risk among patients with truncal vagotomy (HR 0.78, 95% CI 0.55-1.09), which may be driven by truncal vagotomy at least 5 years before PD diagnosis (HR 0.59, 95% CI 0.37-0.93). Selective vagotomy was not related to PD risk in any analyses.
Conclusions:
Although overall vagotomy was not associated the risk of PD, we found suggestive evidence for a potential protective effect of truncal, but not selective, vagotomy against PD development.
Filamentous tau aggregates are hallmark lesions in numerous neurodegenerative diseases, including Alzheimer's disease (AD). Cell culture and animal studies showed that tau fibrils can undergo cell-to-cell transmission and seed aggregation of soluble tau, but this phenomenon was only robustly demonstrated in models overexpressing tau. In this study, we found that intracerebral inoculation of tau fibrils purified from AD brains (AD-tau), but not synthetic tau fibrils, resulted in the formation of abundant tau inclusions in anatomically connected brain regions in nontransgenic mice. Recombinant human tau seeded by AD-tau revealed unique conformational features that are distinct from synthetic tau fibrils, which could underlie the differential potency in seeding physiological levels of tau to aggregate. Therefore, our study establishes a mouse model of sporadic tauopathies and points to important differences between tau fibrils that are generated artificially and authentic ones that develop in AD brains.
Emerging evidence indicates that the pathogenesis of Parkinson's disease (PD) may be due to cell-to-cell transmission of misfolded preformed fibrils (PFF) of α-synuclein (α-syn). The mechanism by which α-syn PFF spreads from neuron to neuron is not known. Here, we show that LAG3 (lymphocyte-activation gene 3) binds α-syn PFF with high affinity (dissociation constant = 77 nanomolar), whereas the α-syn monomer exhibited minimal binding. α-Syn-biotin PFF binding to LAG3 initiated α-syn PFF endocytosis, transmission, and toxicity. Lack of LAG3 substantially delayed α-syn PFF-induced loss of dopamine neurons, as well as biochemical and behavioral deficits in vivo. The identification of LAG3 as a receptor that binds α-syn PFF provides a target for developing therapeutics designed to slow the progression of PD and related α-synucleinopathies. © 2016, American Association for the Advancement of Science. All rights reserved.
Parkinson's disease (PD) is characterized by the progressive appearance of intraneuronal Lewy aggregates, which are primarily composed of misfolded α-synuclein (α-syn). The aggregates are believed to propagate via neural pathways following a stereotypical pattern, starting in the olfactory bulb (OB) and gut. We hypothesized that injection of fibrillar α-syn into the OB of wild-type mice would recreate the sequential progression of Lewy-like pathology, while triggering olfactory deficits. We demonstrate that injected α-syn fibrils recruit endogenous α-syn into pathological aggregates that spread transneuronally over several months, initially in the olfactory network and later in distant brain regions. The seeded inclusions contain posttranslationally modified α-syn that is Thioflavin S positive, indicative of amyloid fibrils. The spreading α-syn pathology induces progressive and specific olfactory deficits. Thus, we demonstrate that propagating α-syn pathology triggered in the OB is functionally detrimental. Collectively, we have created a mouse model of prodromal PD.
Aggregates of abnormal proteins are widely observed in neuronal and glial cells of patients with various neurodegenerative
diseases, and it has been proposed that prion-like behavior of these proteins can account for not only the onset, but also
the progression of these diseases. However, it is not yet clear which abnormal protein structures function most efficiently
as seeds for prion-like propagation. In this study, we aimed to identify the most pathogenic species of α-synuclein (α-syn),
the main component of the Lewy bodies and Lewy neurites that are observed in α-synucleinopathies. We prepared various forms
of α-syn protein and examined their seeding properties in vitro, in cells and in mouse experimental models. We also characterized
these α-syn species by means of electron microscopy and thioflavin fluorescence assays, and found that fragmented beta-sheet-rich
fibrous structures of α-syn with a length of 50 nm or less are the most efficient promoters of accumulation of phosphorylated
α-syn, which is the hallmark of α-synucleinopathies. These results indicate that fragmented amyloid-like aggregates of short
α-syn fibrils are the key pathogenic seeds that trigger prion-like conversion.
Stem cell-based therapy is a potential treatment for neurodegenerative diseases, but its application to Alzheimer’s disease (AD) remains limited. Brain-derived neurotrophic factor (BDNF) is critical in the pathogenesis and treatment of AD. Here, we present a novel therapeutic approach for AD treatment using BDNF-overexpressing neural stem cells (BDNF-NSCs). In vitro, BDNF overexpression was neuroprotective to beta-amyloid-treated NSCs. In vivo, engrafted BDNF-NSCs-derived neurons not only displayed the Ca2+-response fluctuations, exhibited electrophysiological properties of mature neurons and integrated into local brain circuits, but recovered the cognitive deficits. Furthermore, BDNF overexpression improved the engrafted cells’ viability, neuronal fate, neurite complexity, maturation of electrical property and the synaptic density. In contrast, knockdown of the BDNF in BDNF-NSCs diminished stem cell-based therapeutic efficacy. Together, our findings indicate BDNF overexpression improves the therapeutic potential of engrafted NSCs for AD via neurogenic effects and neuronal replacement, and further support the feasibility of NSC-based ex vivo gene therapy for AD.
The progression of pulmonary fibrosis (PF) entails a complex network of interactions between multiple classes of molecules and cells, which are closely related to the vagus nerve. Stimulation of the vagus nerve increases fibrogenic cytokines in humans, therefore, activation of the nerve may promote PF. The hypothesis was tested by comparing the extent and severity of fibrosis in lungs with and without vagal innervation in unilaterally vagotomized mice. The results show that in vagotomized lungs, there were less collagen staining, less severe fibrotic foci (subpleural, peri-vascular and peri-bronchiolar lesions) and destruction of alveolar architecture; decreased collagen deposition (denervated vs intact: COL1α1, 19.1 ± 2.2 vs 22.0 ± 2.6 ng/mg protein; COL1α2, 4.5 ± 0.3 vs 5.7 ± 0.5 ng/mg protein; p < 0.01, n = 21) and protein levels of transforming growth factor beta and interleukin 4; and fewer myofibroblast infiltration (denervated vs intact: 1.2 ± 0.2 vs 3.2 ± 0.6 cells/visual field; p < 0.05, n = 6) and M2 macrophages [though the infiltration of macrophages was increased (denervated vs intact: 112 ± 8 vs 76 ± 9 cells/visual field; p < 0.01, n = 6), the percentage of M2 macrophages was decreased (denervated vs intact: 31 ± 4 vs 57 ± 9%; p < 0.05, n = 5)]. It indicated that the vagus nerve may influence PF by enhancing fibrogenic factors and fibrogenic cells.
Objective:
To summarize evidence on the effects of aquatic therapy on mobility in individuals with neurological diseases.
Data sources:
MEDLINE, EMBASE, PsycInfo, CENTRAL, CINAHL, SPORTDiscus, PEDro, PsycBITE and OT Seeker were searched from inception to 15 September 2014. Hand-searching of reference lists was performed in the selected studies.
Review methods:
The search included randomized controlled trials and quasi-experimental studies that investigated the use of aquatic therapy and its effect on mobility of adults with neurological diseases. One reviewer screened titles and abstracts of retrieved studies from the search strategy. Two reviewers independently examined the full texts and conducted the study selection, data extraction and quality assessment. A narrative synthesis of data was applied to summarize information from included studies. The Downs and Black Scale was used to assess methodological quality.
Results:
A total of 116 articles were obtained for full text eligibility. Twenty studies met the specified inclusion criteria: four Randomized Controlled Trials (RCTs), four non-randomized studies and 12 before-and-after tests. Two RCTs (30 patients with stroke in the aquatic therapy groups), three non-randomized studies and three before-and-after studies showed "fair" evidence that aquatic therapy increases dynamic balance in participants with some neurological disorders. One RCT (seven patients with stroke in the aquatic therapy group) and two before-and-after tests (20 patients with multiple sclerosis) demonstrated "fair" evidence on improvement of gait speed after aquatic therapy.
Conclusion:
Our synthesis showed "fair" evidence supporting the use of aquatic therapy to improve dynamic balance and gait speed in adults with certain neurological conditions.
The cellular hallmarks of Parkinson's disease (PD) are the loss of nigral dopaminergic neurons and the formation of α-synuclein-enriched Lewy bodies and Lewy neurites in the remaining neurons. Based on the topographic distribution of Lewy bodies established after autopsy of brains from PD patients, Braak and coworkers hypothesized that Lewy pathology primes in the enteric nervous system and spreads to the brain, suggesting an active retrograde transport of α-synuclein (the key protein component in Lewy bodies), via the vagal nerve. This hypothesis, however, has not been tested experimentally thus far. Here, we use a human PD brain lysate containing different forms of α-synuclein (monomeric, oligomeric and fibrillar), and recombinant α-synuclein in an in vivo animal model to test this hypothesis. We demonstrate that α-synuclein present in the human PD brain lysate and distinct recombinant α-synuclein forms are transported via the vagal nerve and reach the dorsal motor nucleus of the vagus in the brainstem in a time-dependent manner after injection into the intestinal wall. Using live cell imaging in a differentiated neuroblastoma cell line, we determine that both slow and fast components of axonal transport are involved in the transport of aggregated α-synuclein. In conclusion, we here provide the first experimental evidence that different α-synuclein forms can propagate from the gut to the brain, and that microtubule-associated transport is involved in the translocation of aggregated α-synuclein in neurons.
This protocol describes a primary neuronal model of formation of α-synuclein (α-syn) aggregates that recapitulate features of the Lewy bodies and Lewy neurites found in Parkinson's disease brains and other synucleinopathies. This model allows investigation of aggregate formation, their impact on neuron function, and development of therapeutics. Addition of preformed fibrils (PFFs) synthesized from recombinant α-syn to neurons seeds the recruitment of endogenous α-syn into aggregates characterized by detergent insolubility and hyperphosphorylation. Aggregate formation follows a lag phase of 2-3 d, followed by formation in axons by days 4-7, spread to somatodendritic compartments by days 7-10 and neuron death ∼14 d after PFF addition. Here we provide methods and highlight the crucial steps for PFF formation, PFF addition to cultured hippocampal neurons and confirmation of aggregate formation. Neurons derived from various brain regions from nontransgenic and genetically engineered mice and rats can be used, allowing interrogation of the effect of specific genes on aggregate formation.
The basal ganglia are subcortical nuclei controlling voluntary actions and have been implicated in Parkinson's disease (PD). The prevailing model of basal ganglia function states that two circuits, the direct and indirect pathways, originate from distinct populations of striatal medium spiny neurons (MSNs) and project to different output structures. These circuits are believed to have opposite effects on movement. Specifically, the activity of direct pathway MSNs is postulated to promote movement, whereas the activation of indirect pathway MSNs is hypothesized to inhibit it. Recent findings have revealed that this model might not fully account for the concurrent activation of both pathways during movement. Accordingly, we propose a model in which intrastriatal connections are critical and the two pathways are structurally and functionally intertwined. Thus, all MSNs might either facilitate or inhibit movement depending on the form of synaptic plasticity expressed at a certain moment. In PD, alterations of dopamine-dependent synaptic plasticity could alter this coordinated activity.
A novel test procedure for antidepressants was designed in which a mouse is suspended by the tail from a lever, the movements of the animal being recorded. The total duration of the test (6 min) can be divided into periods of agitation and immobility. Several psychotropic drugs were studied: amphetamine, amitriptyline, atropine, desipramine, mianserin, nomifensine and viloxazine. Antidepressant drugs decrease the duration of immobility, as do psychostimulants and atropine. If coupled with measurement of locomotor activity in different conditions, the test can separate the locomotor stimulant doses from antidepressant doses. Diazepam increases the duration of immobility. The main advantages of this procedure are (1) the use of a simple, objective test situation, (2) the concordance of the results with the validated "behavioral despair" test from Porsolt and, (3) the sensitivity to a wide range of drug doses.
c-Abl is activated in the brain of Parkinson's disease (PD) patients and in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxicated mice where it inhibits parkin through tyrosine phosphorylation leading to the accumulation of parkin substrates, and neuronal cell death. In the present study, we evaluated the in vivo efficacy of nilotinib, a brain penetrant c-Abl inhibitor, in the acute MPTP-induced model of PD. Our results show that administration of nilotinib reduces c-Abl activation and the levels of the parkin substrate, PARIS, resulting in prevention of dopamine (DA) neuron loss and behavioral deficits following MPTP intoxication. On the other hand, we observe no reduction in the tyrosine phosphorylation of parkin and the parkin substrate, AIMP2 suggesting that the protective effect of nilotinib may, in part, be parkin-independent or to the pharmacodynamics properties of nilotinib. This study provides a strong rationale for testing other brain permeable c-Abl inhibitors as potential therapeutic agents for the treatment of PD.
Lewy body (LB) diseases are characterized by alpha-synuclein (AS) aggregates in the central nervous system (CNS). Involvement of the peripheral autonomic nervous system (pANS) is increasingly recognized, although less studied. The aim of this study was to systematically analyze the distribution and severity of AS pathology in the CNS and pANS. Detailed postmortem histopathological study of brain and peripheral tissues from 28 brain bank donors (10 with Parkinson's disease [PD], 5 with dementia with LB [DLB], and 13 with non-LB diseases including atypical parkinsonism and non-LB dementia). AS aggregates were found in the pANS of all 15 LB disease cases (PD, DLB) in stellate and sympathetic ganglia (100%), vagus nerve (86.7%), gastrointestinal tract (86.7%), adrenal gland and/or surrounding fat (53.3%), heart (100%), and genitourinary tract (13.3%), as well as in 1 case of incidental Lewy body disease (iLBD). A craniocaudal gradient of AS burden in sympathetic chain and gastrointestinal tract was observed. DLB cases showed higher amounts of CNS AS aggregates than PD cases, but this was not the case in the pANS. No pANS AS aggregates were detected in Alzheimer's disease (AD) cases with or without CNS AS aggregates. All pathologically confirmed LB disease cases including 1 case of iLBD had AS aggregates in the pANS with a craniocaudal gradient of pathology burden in sympathetic chain and gastrointestinal tract. AS was not detected in the pANS of any AD case. These findings may help in the search of peripheral AS aggregates in vivo for the early diagnosis of PD. © 2013 International Parkinson and Movement Disorder Society.
α-Synuclein accumulation and pathology in Parkinson's disease typically display a caudo-rostral pattern of progression, involving neuronal nuclei in the medulla oblongata at the earliest stages. In this study, selective expression and accumulation of human α-synuclein within medullary neurons was achieved via retrograde transport of adeno-associated viral vectors unilaterally injected into the vagus nerve in the rat neck. The exogenous protein progressively spread toward more rostral brain regions where it could be detected within axonal projections. Propagation to the pons, midbrain and forebrain followed a stereotypical pattern of topographical distribution. It affected areas such as the coeruleus-subcoeruleus complex, dorsal raphae, hypothalamus and amygdala ipsilateral and, to a lesser extent, contralateral to the injection side. Spreading was accompanied by evidence of neuritic pathology in the form of axonal varicosities intensely immunoreactive for human α-synuclein and containing Thioflavin-S-positive fibrils. Thus, overexpression of human α-synuclein in the lower brainstem is sufficient to induce its long-distance caudo-rostral propagation, recapitulating features of Parkinson's disease and mechanisms of disease progression.
Pathological studies on Parkinson's disease (PD) patients suggest that PD pathology progresses from the enteric nervous system (ENS) and the olfactory bulb into the central nervous system. We have previously shown that environmental toxins acting locally on the ENS mimic this PD-like pathology progression pattern in mice. Here, we show for the first time that the resection of the autonomic nerves stops this progression. Moreover, our results show that an environmental toxin (i.e. rotenone) promotes the release of alpha-synuclein by enteric neurons and that released enteric alpha-synuclein is up-taken by presynaptic sympathetic neurites and retrogradely transported to the soma, where it accumulates. These results strongly suggest that pesticides can initiate the progression of PD pathology and that this progression is based on the transneuronal and retrograde axonal transport of alpha-synuclein. If confirmed in patients, this study would have crucial implications in the strategies used to prevent and treat PD.
Parkinson's disease is characterized by abundant α-synuclein (α-Syn) neuronal inclusions, known as Lewy bodies and Lewy neurites, and the massive loss of midbrain dopamine neurons. However, a cause-and-effect relationship between Lewy inclusion formation and neurodegeneration remains unclear. Here, we found that in wild-type nontransgenic mice, a single intrastriatal inoculation of synthetic α-Syn fibrils led to the cell-to-cell transmission of pathologic α-Syn and Parkinson's-like Lewy pathology in anatomically interconnected regions. Lewy pathology accumulation resulted in progressive loss of dopamine neurons in the substantia nigra pars compacta, but not in the adjacent ventral tegmental area, and was accompanied by reduced dopamine levels culminating in motor deficits. This recapitulation of a neurodegenerative cascade thus establishes a mechanistic link between transmission of pathologic α-Syn and the cardinal features of Parkinson's disease.
Parkinson's disease (PD) is the second most common neurodegenerative disorder of aging. The pathological hallmark of PD is neuronal inclusions termed Lewy bodies whose main component is alpha-synuclein protein. The finding of these Lewy bodies in the intestinal enteric nerves led to the hypothesis that the intestine might be an early site of PD disease in response to an environmental toxin or pathogen. One potential mechanism for environmental toxin(s) and proinflammatory luminal products to gain access to mucosal neuronal tissue and promote oxidative stress is compromised intestinal barrier integrity. However, the role of intestinal permeability in PD has never been tested. We hypothesized that PD subjects might exhibit increased intestinal permeability to proinflammatory bacterial products in the intestine. To test our hypothesis we evaluated intestinal permeability in subjects newly diagnosed with PD and compared their values to healthy subjects. In addition, we obtained intestinal biopsies from both groups and used immunohistochemistry to assess bacterial translocation, nitrotyrosine (oxidative stress), and alpha-synuclein. We also evaluated serum markers of endotoxin exposure including LPS binding protein (LBP). Our data show that our PD subjects exhibit significantly greater intestinal permeability (gut leakiness) than controls. In addition, this intestinal hyperpermeability significantly correlated with increased intestinal mucosa staining for E. coli bacteria, nitrotyrosine, and alpha-synuclein as well as serum LBP levels in PD subjects. These data represent not only the first demonstration of abnormal intestinal permeability in PD subjects but also the first correlation of increased intestinal permeability in PD with intestinal alpha–synuclein (the hallmark of PD), as well as staining for gram negative bacteria and tissue oxidative stress. Our study may thus shed new light on PD pathogenesis as well as provide a new method for earlier diagnosis of PD and suggests potential therapeutic targets in PD subjects.
Trial Registration
Clinicaltrials.gov NCT01155492
Parkinson's disease (PD) is characterized by the degeneration of dopamine (DA) neurons in the substantia nigra pars compacta, and motor symptoms including bradykinesia, rigidity, and tremor at rest. These symptoms are exhibited when striatal dopamine concentration has decreased by around 70%. In addition to motor deficits, PD is also characterized by the non-motor symptoms. However, depletion of DA alone in animal models has failed to simultaneously elicit both the motor and non-motor deficits of PD, possibly because the disease is a multi-system disorder that features a profound loss in other neurotransmitter systems. There is growing evidence that additional loss of noradrenaline (NA) neurons of the locus coeruleus, the principal source of NA in the brain, could be involved in the clinical expression of motor as well as in non-motor deficits. In the present review, we analyze the latest evidence for the implication of NA in the pathophysiology of PD obtained from animal models of parkinsonism and from parkinsonian patients. Recent studies have shown that NA depletion alone, or combined with DA depletion, results in motor as well as in non-motor dysfunctions. In addition, by using selective agonists and antagonists of noradrenaline alpha receptors we, and others, have shown that α2 receptors are implicated in the control of motor activity and that α2 receptor antagonists can improve PD motor symptoms as well as l-Dopa-induced dyskinesia. In this review we argue that the loss of NA neurons in PD has an impact on all PD symptoms and that the addition of NAergic agents to dopaminergic medication could be beneficial in the treatment of the disease.
Parkinson disease (PD) is a neurodegenerative disease with motor as well as non-motor signs in the gastrointestinal tract that include dysphagia, gastroparesis, prolonged gastrointestinal transit time, constipation and difficulty with defecation. The gastrointestinal dysfunction commonly precedes the motor symptoms by decades. Most PD is sporadic and of unknown etiology, but a fraction is familial. Among familial forms of PD, a small fraction is caused by missense (A53T, A30P and E46K) and copy number mutations in SNCA which encodes a-synuclein, a primary protein constituent of Lewy bodies, the pathognomonic protein aggregates found in neurons in PD. We set out to develop transgenic mice expressing mutant α-synuclein (either A53T or A30P) from insertions of an entire human SNCA gene as models for the familial disease. Both the A53T and A30P lines show robust abnormalities in enteric nervous system (ENS) function and synuclein-immunoreactive aggregates in ENS ganglia by 3 months of age. The A53T line also has abnormal motor behavior but neither demonstrates cardiac autonomic abnormalities, olfactory dysfunction, dopaminergic neurotransmitter deficits, Lewy body inclusions or neurodegeneration. These animals recapitulate the early gastrointestinal abnormalities seen in human PD. The animals also serve as an in vivo system in which to investigate therapies for reversing the neurological dysfunction that target α-synuclein toxicity at its earliest stages. © The Author 2010. Published by Oxford University Press. For Permissions, please email: [email protected]
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In patients with Parkinson's disease (PD), the associated pathology follows a characteristic pattern involving inter alia the enteric nervous system (ENS), the dorsal motor nucleus of the vagus (DMV), the intermediolateral nucleus of the spinal cord and the substantia nigra, providing the basis for the neuropathological staging of the disease. Here we report that intragastrically administered rotenone, a commonly used pesticide that inhibits Complex I of the mitochondrial respiratory chain, is able to reproduce PD pathological staging as found in patients. Our results show that low doses of chronically and intragastrically administered rotenone induce alpha-synuclein accumulation in all the above-mentioned nervous system structures of wild-type mice. Moreover, we also observed inflammation and alpha-synuclein phosphorylation in the ENS and DMV. HPLC analysis showed no rotenone levels in the systemic blood or the central nervous system (detection limit [rotenone]<20 nM) and mitochondrial Complex I measurements showed no systemic Complex I inhibition after 1.5 months of treatment. These alterations are sequential, appearing only in synaptically connected nervous structures, treatment time-dependent and accompanied by inflammatory signs and motor dysfunctions. These results strongly suggest that the local effect of pesticides on the ENS might be sufficient to induce PD-like progression and to reproduce the neuroanatomical and neurochemical features of PD staging. It provides new insight into how environmental factors could trigger PD and suggests a transsynaptic mechanism by which PD might spread throughout the central nervous system.
Cell-to-cell transmission of proteopathic alpha-synuclein (α-syn) seeds is increasingly thought to underlie the progression of neurodegenerative diseases including Parkinson’s disease, dementia with Lewy bodies, multiple system atrophy, and related synucleinopathies. As such, it is important to understand the chemical and biological relationships between cells and pathological aggregates of α-syn. This brief review updates our understanding of the templated spread of α-syn pathology in neurodegenerative disease from the perspective of proteopathic α-syn seeds, including how these seeds are processed by cells as well as their effects on cellular function. Recent advances in understanding the conformations of α-syn seeds are highlighted, and the possible structural basis for the observed heterogeneity of synucleinopathies is discussed. Finally, we propose the possibility that some known risk factors for synucleinopathies may in fact potentiate the cell-to-cell transmission of α-syn pathology via imbalances in interrelated cell biological processes.
Microbial endocrinology represents the union of microbiology and neurobiology and is concerned with the ability of neurochemicals to serve as an evolutionary-based language between host and microbiota in health and disease. The recognition that microorganisms produce, modify and respond to the same neurochemicals utilized in the various signaling pathways of their mammalian hosts is increasingly being recognized as a mechanism by which the host and microbiota may interact to influence the progression of infectious disease as well as influence behavior through the microbiota-gut-brain axis. While the capacity for bacteria to produce neurochemicals has been recognized for decades, the degree to which this occurs in the environment of the gastrointestinal tract is still poorly understood. By combining techniques used in analytic chemistry, food science and environmental microbiology, a novel culture-based method was developed which generates a medium utilizing animal feed which resembles the contents of the small intestine. The usage of this medium allows for the in vitro growth of bacteria native to the gastrointestinal tract in an environment that is reflective of the small-intestinal host-based milieu. We describe a detailed protocol for the preparation of this medium and the quantification of neurochemicals by microorganisms grown therein. Catecholamines including dopamine and its precursor L-3,4-dihydroxyphenalanine (L-DOPA) as well as biogenic amines including tyramine and its precursor tyrosine, serve as prototypical examples of neurochemicals that are quantifiable with the methods described herein.