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It is quickly becoming apparent that situating human variation in a pathway context is crucial to understanding its phenotypic significance. Toward this end, we have developed a general method for finding pathways associated with traits that control for pathway size. We have applied this method to a new whole genome survey of coding SNP variation i...
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... The NEDD4 protein involved in the pathological process of neurodegeneration diseases, such as Parkinson's, has been found both in animal models (13) and postmortem studies (14). Srinivasan et al. found that rs1912403 in NEDD4 is a risk factor for Parkinson's disease in white people (15), Nonetheless, whether NEDD4 plays a beneficial or detrimental role remains controversial. ...
Background: Neural precursor cell-expressed developmentally downregulated 4 (NEDD4) polymorphisms and childhood trauma (CT) are associated with schizophrenia. However, whether NEDD4 interacts with CT on symptoms of schizophrenia remains unknown. This study aimed to investigate the gene–environment interaction effect.
Methods: We recruited 289 schizophrenia patients and 487 controls and genotyped rs2303579, rs3088077, rs7162435, rs11550869, and rs62043855 in their NEDD4 gene.
Results: We found significant differences in the rs2303579 and rs3088077 between the two groups. Patients with the rs2303579 CC genotype had higher scores compared with other genotype (P = 0.026) in the test of positive schizophrenia syndrome scores, whereas patients with the rs3088077 TT (P = 0.037) and rs7162435 CC genotypes (P = 0.009) had higher scores compared with the other genotypes in the test of excitement factor. Patients with a family history of psychosis (FH+) reported higher negative scores (P = 0.012) than those without. Patients exposed to physical abuse (PA) reported a lower language learning and memory score (P = 0.017) and working memory score (P = 0.047) than those not. Patients exposed to sexual abuse (SA) reported a lower reasoning and problem-solving skills score (P = 0.025); those exposed to emotional neglect (EN) reported a lower social cognition score (P = 0.044); and those exposed to physical neglect reported a lower social cognition score (P = 0.036) but higher visual learning and memory score (P = 0.032). Rs3088077 could interact with EN to increase risk for schizophrenia. Optimal model rs62043855 × EA, rs3088077 × rs7162435 × rs11550869 × SA × EN and rs2303579 × rs7162435 × rs11550869 × rs62043855 × EA × PA could explain positive symptom, excitement symptom and working memory, respectively, in FH+ group.
Conclusion: The study highlighted that the combined interaction of NEDD4 and CT may be associated with symptoms of schizophrenia especially for those with FH+.
... Interestingly, smoking and HLA-DRB1 appear to be involved in common pathways possibly related to neuroinflammation (Chuang et al., 2017). Srinivasan et al. (2009) first developed a general method for finding molecular pathways associated with clinical traits. These authors found that variation in T cell receptor signaling pathways may have value in predicting PD susceptibility (Srinivasan et al., 2009). ...
... Srinivasan et al. (2009) first developed a general method for finding molecular pathways associated with clinical traits. These authors found that variation in T cell receptor signaling pathways may have value in predicting PD susceptibility (Srinivasan et al., 2009). In addition, Kannarkat et al. (2015) revealed that the MHC class II locus may increase susceptibility to PD possibly by modulating the CD4+ T cell response (Kannarkat et al., 2015). ...
... Second, we revealed that the different T cell population profiles are correlated with the clinical manifestations and disease severity (Kustrimovic et al., 2016;Saunders et al., 2012). Third, genetic studies have revealed that the adaptive immune system, especially T cell signaling, is genetically associated with PD (Gagliano et al., 2016;Srinivasan et al., 2009). Fourth, studies have shown that in familial and sporadic PD patients, autoantigens exist and may induce autoimmune T cell responses (Matheoud et al., 2016;Sulzer et al., 2017). ...
Recent evidence has shown that neuroinflammation plays a key role in the pathogenesis of Parkinson's disease (PD). However, different components of the brain's immune system may exert diverse effects on neuroinflammatory events in PD. The adaptive immune response, especially the T cell response, can trigger type 1 pro-inflammatory activities and suppress type 2 anti-inflammatory activities, eventually resulting in deregulated neuroinflammation and subsequent dopaminergic neurodegeneration. Additionally, studies have increasingly shown that therapies targeting T cells can alleviate neurodegeneration and motor behavior impairment in animal models of PD. Therefore, we conclude that abnormal T cell-mediated immunity is a fundamental pathological process that may be a promising translational therapeutic target for Parkinson's disease.
... Interestingly, NEDD4 staining is very strong in nigral neurons containing Lewy bodies (LB) in the human Substantia Nigra (SN) and the Locus Coeruleus (LC) from patients with LB pathologies [15]. Furthermore, NEDD4 presents a single nucleotide polymorphism (SNP) that has been associated with a major risk factor for sporadic PD in a whole genome association study (GWAS) [17]. Here, we identify NEDD4 as a novel E3 ubiquitin ligase for RTP801, controlling its homeostasis. ...
Parkinson's disease (PD) is a disorder characterized by the degeneration of certain neuronal populations in the central and peripheral nervous system. One of the hallmarks of the disease is the toxic accumulation of proteins within susceptible neurons due to major impairment in the degradation/clearance protein systems.
RTP801 is a pro-apoptotic protein that is sufficient and necessary to induce neuronal death in cellular and animal models of PD. RTP801 is also upregulated in sporadic and parkin mutant PD brains. Here, we report the role of NEDD4, an E3 ligase involved in α-synuclein degradation and PD pathogenesis, in the regulation of RTP801 protein levels and toxicity. NEDD4 polyubiquitinates RTP801 in a cell-free system and in cellular cultures, and they interact physically. NEDD4 conjugates K63-ubiquitin chains to RTP801 and targets it for degradation. NEDD4 regulates RTP801 protein levels in both cultured cells and in the brain tissue. NEDD4 levels are diminished in nigral neurons from human PD brains. Interestingly, neurotoxin 6-OHDA decreases dramatically NEDD4 protein expression but elevates RTP801 protein levels. Moreover, NEDD4 protects neuronal PC12 cells from both 6-OHDA and RTP801-induced toxicity. In primary cortical neurons, NEDD4 knockdown toxicity is mediated by RTP801 since the double knockdown of RTP801 and NEDD4 abrogates the loss of phospho Ser473-Akt and the appearance of caspase-cleaved spectrin fragments.
Thus, NEDD4 ligase regulates RTP801 and is sensitive to PD-associated oxidative stress. This suggests that NEDD4 loss of function in PD could contribute importantly into neuronal death by elevating RTP801.
... This can also be seen in a number of PD rodent models such as models based on overexpression of the mutated A53T human α-synuclein (SNCA) protein (Chung et al., 2009), or overexpression of two LRRK2 mutations (G2029S and R1441G) (Li et al., 2009;MacLeod et al., 2006), as well as MPTP toxicity models (Burke and O'Malley, 2013;Korecka et al., 2013). Gene expression studies (Bossers et al., 2009), genome wide association studies (GWAS) of single-nucleotide polymorphism (SNP) variations (Kim et al., 2011;Lin et al., 2009;Maraganore et al., 2005;Srinivasan et al., 2009) and pathway analysis studies (Edwards et al., 2011;Lesnick et al., 2007;Sutherland et al., 2009) identified axon guidance signaling pathways to be associated with PD development. Through comparison of GWAS and pathway analyses, five axon guidance genes were identified to be significantly associated with the development of PD pathology: DCC, EPHB1, NTNG1, SEMA5A and SLIT3 (Lin et al., 2009). ...
Modeling neurological diseases using human embryonic or patient-derived induced pluripotent stem cells (iPSC) improves the understanding of molecular and cellular changes underlying these diseases and can lead to new, potentially personalized therapies. Changes in expression of axon guidance cues and altered cytoskeletal maintenance have been implicated in neurodegenerative and neuropsychiatric disorders. To date, most of the iPSC patient-derived cellular dysfunction and phenotypic studies have been performed in vitro. To study the intrinsic axonal impairments and neuronal connectivity deficits in human disease iPSC-derived neurons we propose to graft these cells into the physiological three-dimensional multi-structural environment of the central nervous system of rodent models to obtain relevant in vivo data. Such human iPSC in vivo chimeric models can allow for neuronal maturation, capture neuropathological phenotypes of axonal and connectivity impairments, and serve as target engagement and drug validation studies using human cells, thus highly relevant for advancement of the drug development process in the late pre-clinical stages.
... A role for Nedd4 in the human condition is supported by the identification of a coding SNP as a risk factor for idiopathic PD (Srinivasan et al., 2009), the finding that Nedd4 mRNA expression is increased in brain regions with Lewy body pathology (Dumitriu et al., 2012) and our neuropathological observations that Nedd4 is up-regulated in a subpopulation of pigmented neurons containing Lewy bodies (Tofaris et al., 2011). Since Nedd4 is a ubiquitin ligase that functions in the endosomal-lysosomal pathway, our data are also consistent with other studies which have implicated this pathway in PD pathogenesis (Dodson et al., 2012) and genetic screens showing that genetic Fig. 2. Increased neuronal Nedd4 reduces α-synuclein levels in the Drosophila brain. ...
Parkinson's disease is a neurodegenerative disorder, characterised by accumulation and misfolding of α-synuclein. Although the level of α-synuclein in neurons is fundamentally linked to the onset of neurodegeneration, multiple pathways have been implicated in its degradation, and it remains unclear which are the critical ubiquitination enzymes that protect against α-synuclein accumulation in vivo. The ubiquitin ligase Nedd4 targets α-synuclein to the endosomal-lysosomal pathway in cultured cells. Here we asked whether Nedd4-mediated degradation protects against α-synuclein-induced toxicity in the Drosophila and rodent models of Parkinson's disease. We show that overexpression of Nedd4 can rescue the degenerative phenotype from ectopic expression of α-synuclein in the Drosophila eye. Overexpressed Nedd4 in the Drosophila brain, prevented the α-synuclein-induced locomotor defect whereas reduction in endogenous Nedd4 by RNAi led to worsening motor function and increased loss of dopaminergic neurons. Accordingly, AAV-mediated expression of wild-type but not the catalytically inactive Nedd4 decreased the α-synuclein-induced dopaminergic cell loss in the rat substantia nigra and reduced α-synuclein accumulation. Collectively, our data in two evolutionarily distant model organisms strongly suggest that Nedd4 is a modifier of α-synuclein pathobiology and thus a potential target for small molecule activators.
... Building on approaches originally developed in the context of microarray gene expression experiments, the common theme in the pathway analysis approaches is that they examine whether a group of related loci in the same biological pathway are jointly associated with a trait of interest. In line with the observations in microarray gene expression studies, it has been shown that in those cases where there is only a modest overlap in the variant or gene-level findings between different studies, due to factors such as differences in the genetic structure, the pathway-level associations may be much more reproducible even between different study populations57585960. These findings support the concept that individuals with the same disease phenotype may have marked interindividual genetic heterogeneity in the sense that their disease predisposing variants may lie in distinct loci within the same or related pathways [14] . ...
A central challenge in systems biology and medical genetics is to understand how interactions among genetic loci contribute to complex phenotypic traits and human diseases. While most studies have so far relied on statistical modeling and association testing procedures, machine learning and predictive modeling approaches are increasingly being applied to mining genotype-phenotype relationships, also among those associations that do not necessarily meet statistical significance at the level of individual variants, yet still contributing to the combined predictive power at the level of variant panels. Network-based analysis of genetic variants and their interaction partners is another emerging trend by which to explore how sub-network level features contribute to complex disease processes and related phenotypes. In this review, we describe the basic concepts and algorithms behind machine learning-based genetic feature selection approaches, their potential benefits and limitations in genome-wide setting, and how physical or genetic interaction networks could be used as a priori information for providing improved predictive power and mechanistic insights into the disease networks. These developments are geared toward explaining a part of the missing heritability, and when combined with individual genomic profiling, such systems medicine approaches may also provide a principled means for tailoring personalized treatment strategies in the future.
... Such effects have been identified in other complex disorders both when the analysis was limited to genes containing robustly associated SNPs (29 -32) and also when the analysis was expanded to include genes containing SNPs whose evidence for association fell short of stringent genome-wide significant thresholds (30,32,33). To date, biological pathway-based analysis in PD has been limited to relatively small GWA data sets, and has implicated the axon guidance pathway as being relevant to PD (34), a finding that was recently replicated in a small independent data set (35). ...
... These findings imply that genetic variation in genes related to these biological processes has a role in increasing susceptibility to PD and is, therefore, a potential mechanism that should be the subject of further detailed genetic and functional analyses. Although in this study we were unable to replicate the previous reports of an enrichment of association signal in genes involved in axon guidance (34,35), it is worth noting that the T-cell receptor signalling pathway [Kyoto Encyclopedia of Genes and Genomes (KEGG) 04660] has previously been implicated in PD pathology by pathway analysis of GWA data (35). Clearly, the validity of our analysis is dependent on the quality with which biological categories are annotated and that this is likely to be variable. ...
... These findings imply that genetic variation in genes related to these biological processes has a role in increasing susceptibility to PD and is, therefore, a potential mechanism that should be the subject of further detailed genetic and functional analyses. Although in this study we were unable to replicate the previous reports of an enrichment of association signal in genes involved in axon guidance (34,35), it is worth noting that the T-cell receptor signalling pathway [Kyoto Encyclopedia of Genes and Genomes (KEGG) 04660] has previously been implicated in PD pathology by pathway analysis of GWA data (35). Clearly, the validity of our analysis is dependent on the quality with which biological categories are annotated and that this is likely to be variable. ...
Parkinson's disease (PD) is the second most common neurodegenerative disease affecting 1-2% in people over 60 and 3-4% in people over 80. Genome-wide association (GWA) studies have now implicated significant evidence for association in at least 18 genomic regions. We have studied a large PD-meta analysis and identified a significant excess of SNPs (p<1x10(-16)) that are associated with PD but fall short of the genome-wide significance threshold. This result was independent of variants at the 18 previously implicated regions and implies the presence of additional polygenic risk alleles. To understand how these loci increase risk of PD we applied a pathway based analysis, testing for biological functions that were significantly enriched for genes containing variants associated with PD. Analysing two independent GWA studies, we identified that both had a significant excess in the number of functional categories enriched for PD associated genes (minimum p=0.014 and p=0.006 respectively). Moreover, 58 categories were significantly enriched for associated genes in both GWA studies (p<0.001) implicating genes involved in the regulation of leukocyte/lymphocyte activity and also cytokine mediated signalling as conferring an increased susceptibility to PD. These results were unaltered by the exclusion of all 178 genes that were present at the 18 genomic regions previously reported to be strongly associated with PD (including the HLA locus). Our findings therefore provide independent support to the strong association signal at the HLA locus and imply that the immune related genetic susceptibility to PD is likely to be more widespread in the genome than previously appreciated.
... The majority of patients suffer from non-mendelian forms of PD which are likely to be caused by the combined effects of genetic and environmental factors. More than 800 published genome-wide association studies have implicated dozen of potential risk loci in Parkinson's Disease most of them providing inconclusing or conflicting results except for a few polymorphisms in SCNA, LRRK2, MAPT, GBA genes [71][72][73]. Marked interindividual variability in dopaminergic antiparkinsonian drug response and the occurrence of adverse events, especially motor and psychotropic, has also prompted the search for genetic determinants. With respect to potential associations between allelic variants and occurrence of adverse drug reaction or response, the majority of studies have not been replicated. ...
The analysis of human genetic variability can lead to the comprehension of medical issues and to the development of personalized therapeutic protocols. Single nucleotide polymorphisms, are the most common type of human genetic variation and have been associated to disease development and phenotype forecasting. The recent technologies for DNA sequencing and bioinformatic analysis are now giving the opportunity to develop new diagnostic and prevention approaches also through health promotion protocols. The genetic data management is at the same time underlining technical limitations and old ethical issues.
... This is also demonstrated for the LRRK2 homolog in C. elegans (LRK-1) which is involved in regulation of the axonal-dendritic polarity of synaptic vesicle proteins (Sakaguchi-Nakashima et al., 2007). Other studies suggest that axon-guidance pathway genes (such as EFN and SLIT) might predispose to PD (Lesnick et al., 2007;Lin et al., 2009;Srinivasan et al., 2009). In this view, we also observed EFNA2 (ephrin-A2), EPH receptor A3 and SLIT3 dysregulations in LRRK2 G2019S PBMCs. ...
... These regulatory T cells modulate microglial inflammation through IL-10-and TGF--mediated mechanisms (Reynolds et al., 2007). Supporting evidence for the importance of the immune system in PD have also come from a whole genome association study suggesting genetic variations in the T cell receptor signalling pathway as a potential susceptibility factor of PD (Srinivasan et al., 2009). These data, together with the dysregulated canonical pathways we observed here in PBMCs from mutated LRRK2 carriers, indicate that we should further decipher the mechanisms controlling immune homeostasis in PD patients. ...
To gain insight into systemic molecular events associated with an age-related neurodegenerative disorder, we compared gene expression patterns in peripheral blood mononuclear cells (PBMCs) sampled from elderly, healthy controls and from Parkinson's disease (PD) patients carrying the most frequently found mutation of the LRRK2 gene (G2019S). A transcriptomic approach enabled us to detect differentially expressed genes and revealed perturbations of pathways known to be involved in PD-related neurodegeneration: the ubiquitin-proteasome system, the mitochondrial oxidation system, inflammation, axonal guidance, calcium signalling and apoptosis. Moreover, alterations of the MAP kinase pathway, the actin cytoskeleton, the ephrin receptor system and vesicular transport - all recently associated with the LRRK2 G2019S mutation pathogenesis - were noted. Furthermore, we acquired new evidences of dysregulation in leukocyte extravasation signalling and immune system pathways in PD. These data show that the G2019S mutation affects the entire body and highlight some of the molecular events observed in the brain. This PBMC transcriptomic approach could be used to better understand neurodegeneration in PD and decipher new pathogenetic mechanisms, even at early stages of the disease.
... The most immediate challenge, following GWAS, will be to identify genomic pathways related to PD and to understand the pathobiological consequences of risk variants (351,595). A major aim will be to understand how genetic susceptibility factors interact with each other and with environmental factors to cause disease. ...
Parkinson's disease (PD) is a common motor disorder of mysterious etiology. It is due to the progressive degeneration of the dopaminergic neurons of the substantia nigra and is accompanied by the appearance of intraneuronal inclusions enriched in α-synuclein, the Lewy bodies. It is becoming increasingly clear that genetic factors contribute to its complex pathogenesis. Over the past decade, the genetic basis of rare PD forms with Mendelian inheritance, representing no more than 10% of the cases, has been investigated. More than 16 loci and 11 associated genes have been identified so far; genome-wide association studies have provided convincing evidence that polymorphic variants in these genes contribute to sporadic PD. The knowledge acquired of the functions of their protein products has revealed pathways of neurodegeneration that may be shared between inherited and sporadic PD. An impressive set of data in different model systems strongly suggest that mitochondrial dysfunction plays a central role in clinically similar, early-onset autosomal recessive PD forms caused by parkin and PINK1, and possibly DJ-1 gene mutations. In contrast, α-synuclein accumulation in Lewy bodies defines a spectrum of disorders ranging from typical late-onset PD to PD dementia and including sporadic and autosomal dominant PD forms due to mutations in SCNA and LRRK2. However, the pathological role of Lewy bodies remains uncertain, as they may or may not be present in PD forms with one and the same LRRK2 mutation. Impairment of autophagy-based protein/organelle degradation pathways is emerging as a possible unifying but still fragile pathogenic scenario in PD. Strengthening these discoveries and finding other convergence points by identifying new genes responsible for Mendelian forms of PD and exploring their functions and relationships are the main challenges of the next decade. It is also the way to follow to open new promising avenues of neuroprotective treatment for this devastating disorder.
