[Show abstract][Hide abstract]ABSTRACT: All living organisms have evolutionarily adapted themselves to the Earth’s gravity, and failure to adapt to gravity changes may lead to pathological conditions. This perspective may also apply to abnormal aging observed in bedridden elderly patients with aging-associated diseases such as osteoporosis and sarcopenia. Given that bedridden elderly patients are partially analogous to astronauts in that both cannot experience the beneficial effects of gravity on the skeletal system and may suffer from bone loss and muscle weakness, one may wonder whether there are gravity-related mechanisms underlying diseases among the elderly. In contrast to numerous studies of the relevance of microgravity in skeletal disorders, little attention has been paid to neurodegenerative diseases. Therefore, the objective of this paper is to discuss the possible relevance of microgravity in these diseases. We particularly noted a proteomics paper showing that levels of hippocampal proteins, including β-synuclein and carboxyl-terminal ubiquitin hydrolase L1, which have been linked to familial neurodegenerative diseases, were significantly decreased in the hippocampus of mice subjected to hindlimb suspension, a model of microgravity. We suggest that microgravity-induced neurodegeneration may be further exacerbated by diabetes and other factors. On the basis of this view, prevention of neurodegenerative diseases through ‘anti-diabetes’ and ‘hypergravity’ approaches may be important as a common therapeutic approach on Earth and in space. Collectively, neurodegenerative diseases and space medicine may be linked to each other more strongly than previously thought.
[Show abstract][Hide abstract]ABSTRACT: Alzheimer's disease (AD) is the most common form of dementia. The pathological hallmarks of AD are amyloid plaques [aggregates of amyloid-beta (Aβ)] and neurofibrillary tangles (aggregates of tau). Growing evidence suggests that tau accumulation is pathologically more relevant to the development of neurodegeneration and cognitive decline in AD patients than Aβ plaques. Oxidative stress is a prominent early event in the pathogenesis of AD and is therefore believed to contribute to tau hyperphosphorylation. Several studies have shown that the autophagic pathway in neurons is important under physiological and pathological conditions. Therefore, this pathway plays a crucial role for the degradation of endogenous soluble tau. However, the relationship between oxidative stress, tau protein hyperphosphorylation, autophagy dysregulation, and neuronal cell death in AD remains unclear. Here, we review the latest progress in AD, with a special emphasis on oxidative stress, tau hyperphosphorylation, and autophagy. We also discuss the relationship of these three factors in AD.
Full-text Article · Jul 2015 · Oxidative Medicine and Cellular Longevity
[Show abstract][Hide abstract]ABSTRACT: Gaucher disease is associated with Parkinson's disease (PD) by mutations in glucocerebrosidase (GCase). The gene encoding GCase, glucosidase beta acid (GBA), is an important risk factor for PD. Findings from large studies have shown that patients with PD have an increased frequency of mutations in GBA and that GBA mutation carriers exhibit diverse parkinsonian phenotypes and Lewy body pathology. Although the mechanism for this association remains elusive, some hypotheses have been proposed to explain it, including gain of function caused by GBA mutations, which increases α-synuclein (α-syn) aggregation, loss of function due to lysosomal enzyme deficiency, which affects α-syn clearance, and even a bidirectional feedback loop, but each of these hypotheses has its limitations. It is also worth noting that many findings have implicated the interaction between α-syn and GCase, indicating the essential role of the interaction in the pathogenesis of GBA-associated parkinsonism. Therefore, the current review focuses on α-syn and GCase, and it provides some new thoughts that may be helpful for understanding the α-syn-GCase interaction and unraveling the exact mechanism underlying GBA-associated parkinsonism.
Article · Mar 2015 · Cellular and Molecular Neurobiology
[Show abstract][Hide abstract]ABSTRACT: The discovery of α-synuclein (αS) mutations has made a major contribution to the understanding of the pathogenesis of α-synucleinopathies such as Parkinson's disease and dementia with Lewy bodies (DLB). In contrast, less attention has been paid to β-synuclein (βS) mutations. In this paper, we show that transgenic (tg) mice expressing DLB-linked P123H βS develop progressive neurodegeneration, as characterized by axonal swelling, astrogliosis and behavioural abnormalities, with memory disorder being more prominent than motor deficits. Furthermore, cross-breeding of P123H βS tg mice with αS tg mice, but not with αS knockout mice, greatly enhanced neurodegeneration phenotypes. These results suggest that P123H βS is pathogenic and cooperates with pathogenic αS to stimulate neurodegeneration in mouse brain, indicating a causative role of P123H βS in familial DLB. Given the neuritic pathology of βS in sporadic α-synucleinopathies, it appears that alteration of βS can contribute to the pathogenesis of a broad range of α-synucleinopathies.
Full-text Article · Nov 2010 · Nature Communications
[Show abstract][Hide abstract]ABSTRACT: Gangliosides are abundantly expressed in the nervous system, and deregulated expression or activity of gangliosides is associated with the progression of various disorders, including lysosomal storage diseases, Guillain-Barre syndrome and Alzheimer disease. By contrast, previous studies show that GM1 ganglioside may act in a protective manner in the drug (e.g., MPTP and 6-OHDA)-induced Parkinsonian models, although the precise mechanisms have not been well addressed. In our recent publication, dementia with Lewy bodies (DLB)-linked neuroblastoma cells were treated with D-Threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP), an inhibitor of glycosyl ceramide synthetase. These PDMP-treated cells develop lysosomal diseases characterized by reduced lysosomal activity, enhanced lysosomal permeability and cytotoxicity. Furthermore, PDMP-mediated inhibition of autophagy-lysosomal pathway result in both accumulation of alpha-synuclein and mutant beta-synuclein. Finally, these phenotypes are reversed by ganglioside treatment. Taken together, our results suggest that endogenous gangliosides may play a protective role against the lysosomal pathology of synucleinopathies.
[Show abstract][Hide abstract]ABSTRACT: Gangliosides may be involved in the pathogenesis of Parkinson's disease and related disorders, although the precise mechanisms governing this involvement remain unknown. In this study, we determined whether changes in endogenous ganglioside levels affect lysosomal pathology in a cellular model of synucleinopathy. For this purpose, dementia with Lewy body-linked P123H beta-synuclein (beta-syn) neuroblastoma cells transfected with alpha-synuclein were used as a model system because these cells were characterized as having extensive formation of lysosomal inclusions bodies. Treatment of these cells with D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP), an inhibitor of glycosyl ceramide synthase, resulted in various features of lysosomal pathology, including compromised lysosomal activity, enhanced lysosomal membrane permeabilization, and increased cytotoxicity. Consistent with these findings, expression levels of lysosomal membrane proteins, ATP13A2 and LAMP-2, were significantly decreased, and electron microscopy demonstrated alterations in the lysosomal membrane structures. Furthermore, the accumulation of both P123H beta-syn and alpha-synuclein proteins was significant in PDMP-treated cells because of the suppressive effect of PDMP on the autophagy pathway. Finally, the detrimental effects of PDMP on lysosomal pathology were significantly ameliorated by the addition of gangliosides to the cultured cells. These data suggest that endogenous gangliosides may play protective roles against the lysosomal pathology of synucleinopathies.
Full-text Article · May 2009 · American Journal Of Pathology
[Show abstract][Hide abstract]ABSTRACT: Recently, autophagy has been associated with the TLR signaling pathway to eliminate intracellular pathogens in the innate immune system. However, it is unknown if other pathways regulate autophagy during the immunologic response. Given the critical role of the purinergic P2X7 receptor (P2X7R) pathway during various immunologic functions (i.e., caspase activation and IL-1beta secretion), the principal objective here was to determine whether the P2X7R pathway may regulate autophagy in immune cells. We observed in both MG6 mouse microglial cells and primary microglia that activation of P2X7R by ATP increases the expression of microtubule-associated protein 1 light chain 3 (LC3)-II, the autophagosomal membrane-associated form of LC3, in an extracellular Ca(2+)-dependent manner. Consistent with this, immunohistochemistry showed extensive formation of LC3-immunopositive dots, and electron microscopy demonstrated accumulation of autophagosomes and autophagolysosomes in ATP-treated cells. Importantly, the up-regulation of LC3-II by P2X7R activation was not affected by autophagy inhibitors, such as 3-methyladenine and PI3K inhibitors. Furthermore, while lysosomal functions were impaired by ATP treatment, autophagolysosomal components were released into the extracellular space. Similarly, a phagocytosis assay using Escherichia coli BioParticles showed that phagosome maturation was impaired in ATP-treated cells and a robust release of LC3-immunopositive phagolysosomes was induced along with a radial extension of microtubule bundles. Taken together, the data suggest a novel mechanism whereby the P2X7R signaling pathway may negatively regulate autophagic flux through the impairment of lysosomal functions, leading to stimulation of a release of autophagolysosomes/phagolysosomes into the extracellular space.
Full-text Article · Mar 2009 · The Journal of Immunology
[Show abstract][Hide abstract]ABSTRACT: Two missense mutations (P123H and V70M) of beta-synuclein (beta-syn), the homologue of alpha-syn, have been recently identified in dementia with Lewy bodies. However, the mechanism through which these mutations influence the pathogenesis of dementia with Lewy bodies is unclear. To investigate the role of the beta-syn mutations in neurodegeneration, each mutant was stably transfected into B103 neuroblastoma cells. Cells overexpressing mutated beta-syn had eosinophilic cytoplasmic inclusion bodies immunopositive for mutant beta-syn, and electron microscopy revealed that these cells were abundant in various cytoplasmic membranous inclusions resembling the histopathology of lysosomal storage disease. Consistent with these findings, the inclusion bodies were immunopositive for lysosomal markers, including cathepsin B, LAMP-2, GM2 ganglioside, and ATP13A2, which has recently been linked to PARK9. Notably, formation of these lysosomal inclusions was greatly stimulated by co-expression of alpha-syn, was dependent on the phosphorylation of alpha-syn at Ser-129, and was more efficient with the A53T familial mutant of alpha-syn compared with wild type. Furthermore, the inclusion formation in cells overexpressing mutant beta-syn and transfected with alpha-syn was significantly suppressed by treatment with autophagy-lysosomal inhibitors, which were associated with impaired clearance of syn proteins and enhanced apoptosis, indicating that formation of lysosomal inclusions might be protective. Collectively, the results demonstrated unambiguously that overexpression of beta-syn mutants (P123H and V70M) in neuroblastoma cells results in an enhanced lysosomal pathology. We suggest that these missense mutations of beta-syn might play a causative role in stimulating neurodegeneration.
Full-text Article · Oct 2007 · Journal of Biological Chemistry
[Show abstract][Hide abstract]ABSTRACT: DJ-1 is a multifunctional protein whose loss of function by gene mutations may play a causative role for familial Parkinson's disease (PD). A recent study has shown that the expression of this molecule is upregulated in both brains and cerebrospinal fluids (CSF) in various neurological disorders, including sporadic PD, Alzheimer's disease (AD) and stroke, raising a possibility that DJ-1 could be a potential biomarker for these diseases. In this context, the main objective of the present study was to determine if DJ-1 was increased in the plasma of PD patients. For this purpose, blood plasma samples collected from sporadic PD patients, dementia with Lewy bodies (DLB) and healthy age-matched controls were analyzed by immunoblotting and enzyme-linked immunosorbent assay. The results showed that the plasma DJ-1 levels in PD (n=104) were higher than those in control (n=80) (p<0.05). Moreover, the plasma DJ-1 levels in the advanced stage of PD (n=52, Yahr III-IV) were higher than those in the early stage of PD (n=52, Yahr I-II) (p<0.05), demonstrating that the plasma DJ-1 was correlated with the disease severity in PD. Plasma DJ-1 levels were also significantly higher in DLB (n=30) compared with both controls and early stage of PD (p<0.01). Taken together, these results suggest that the plasma DJ-1 could be a useful biomarker for the evaluation of the disease severity in PD and possibly in other Lewy body diseases.
[Show abstract][Hide abstract]ABSTRACT: The present study investigated expression of alpha-synuclein (alpha-syn), a presynaptic protein involved in the pathogenesis of Parkinson's disease, in erythroid cells. Using various immunological procedures, immunoreactivity of alpha-syn was unambiguously demonstrated in erythroid lineage in murine bone marrows and peripheral erythrocytes. Expression of alpha-syn mRNA was also confirmed by in situ hybridization. Furthermore, flow cytometry analysis revealed that approximately 80% of erythroid cells in murine bone marrows expressed alpha-syn, while more than 90% of peripheral erythrocytes expressed alpha-syn. Nonetheless, alpha-syn null mice exhibited apparently no phenotypic changes in erythroid cells as was the case in their brains, suggesting that there might be underlying some redundant mechanisms. Together with previous reports showing the expression of alpha-syn in lymphocytes and platelets, the present finding supports a contention that alpha-syn might play some important functions in hematopoietic system.
Full-text Article · Jul 2007 · Biochemical and Biophysical Research Communications
[Show abstract][Hide abstract]ABSTRACT: Because a limited study previously showed that alpha-synuclein (alpha-syn), the major pathogenic protein for Parkinson disease, was expressed in differentiating brain tumors as well as various peripheral cancers, the main objective of the present study was to determine whether alpha-syn might be involved in the regulation of tumor differentiation. For this purpose, alpha-syn and its non-amyloidogenic homologue beta-syn were stably transfected to human osteosarcoma MG63 cell line. Compared with beta-syn-overexpressing and vector-transfected cells, alpha-syn-overexpressing cells exhibited distinct features of differentiated osteoblastic phenotype, as shown by up-regulation of alkaline phosphatase and osteocalcin as well as inductive matrix mineralization. Further studies revealed that proteasome activity was significantly decreased in alpha-syn-overexpressing cells compared with other cell types, consistent with the fact that proteasome inhibitors stimulate differentiation of various osteoblastic cells. In alpha-syn-overexpressing cells, protein kinase C (PKC) activity was significantly decreased, and reactivation of PKC by phorbol ester significantly restored the proteasome activity and abrogated cellular differentiation. Moreover, activity of lysosome was up-regulated in alpha-syn-overexpressing cells, and treatment of these cells with autophagy-lysosomal inhibitors resulted in a decrease of proteasome activity associated with up-regulation of alpha-syn expression, leading to enhance cellular differentiation. Taken together, these results suggest that the stimulatory effect of alpha-syn on tumor differentiation may be attributed to down-regulation of proteasome, which is further modulated by alterations of various factors, such as protein kinase C signaling pathway and a autophagy-lysosomal degradation system. Thus, the mechanism of alpha-syn regulation of tumor differentiation and neuropathological effects of alpha-syn may considerably overlap with each other.
Full-text Article · Mar 2007 · Journal of Biological Chemistry
[Show abstract][Hide abstract]ABSTRACT: Because a limited study previously showed that α-synuclein (α-syn), the major pathogenic protein for Parkinson disease, was
expressed in differentiating brain tumors as well as various peripheral cancers, the main objective of the present study was
to determine whether α-syn might be involved in the regulation of tumor differentiation. For this purpose, α-syn and its non-amyloidogenic
homologue β-syn were stably transfected to human osteosarcoma MG63 cell line. Compared with β-syn-overexpressing and vector-transfected
cells, α-syn-overexpressing cells exhibited distinct features of differentiated osteoblastic phenotype, as shown by up-regulation
of alkaline phosphatase and osteocalcin as well as inductive matrix mineralization. Further studies revealed that proteasome
activity was significantly decreased in α-syn-overexpressing cells compared with other cell types, consistent with the fact
that proteasome inhibitors stimulate differentiation of various osteoblastic cells. In α-syn-overexpressing cells, protein
kinase C (PKC) activity was significantly decreased, and reactivation of PKC by phorbol ester significantly restored the proteasome
activity and abrogated cellular differentiation. Moreover, activity of lysosome was up-regulated in α-syn-overexpressing cells,
and treatment of these cells with autophagy-lysosomal inhibitors resulted in a decrease of proteasome activity associated
with up-regulation of α-syn expression, leading to enhance cellular differentiation. Taken together, these results suggest
that the stimulatory effect of α-syn on tumor differentiation may be attributed to down-regulation of proteasome, which is
further modulated by alterations of various factors, such as protein kinase C signaling pathway and a autophagy-lysosomal
degradation system. Thus, the mechanism of α-syn regulation of tumor differentiation and neuropathological effects of α-syn
may considerably overlap with each other.
Article · Feb 2007 · Journal of Biological Chemistry
[Show abstract][Hide abstract]ABSTRACT: Previous studies have shown that beta-synuclein (beta-syn), the homologue of alpha-syn, inhibited alpha-syn aggregation and stabilized Akt cell survival signaling molecule, suggesting that beta-syn was protective against alpha-syn-related neurodegenerative disorders, such as Parkinson's disease and diffuse Lewy body disease. However, emerging evidence argues that the situation may be not so simple. Two missense mutations of beta-syn were identified in familial and sporadic diffuse Lewy body disease, and wild type beta-syn was induced to form fibril structures in vitro, while, alpha-syn was shown to be protective against neurodegeneration caused by deletion of cysteine-string protein-alpha, the presynaptic cochaperone to Hsc70 in mice. Collectively, alpha- and beta-syn are both, but in varying degrees, featured with two opposite properties, namely normal chaperone and anti-chaperone. By reviewing recent progress in syn biology with a particular focus on beta-syn, this manuscript refers to the intriguing possibility that the dual syn proteins might have acquired a driving force for synaptic evolution. Hypothetically, the anti-chaperone syn may provoke stress-induced diverse responses, whereas, the chaperone syn may provide buffering for them, allowing accumulation of nonlethal phenotypic variations in synapses. Consequently, dual syn proteins may cope with forthcoming stresses in the brain by stimulating adaptive evolution. In this context, failure to regulate this process due to various causes, such as gene mutations and environmental risk factors, may result in imperfect adaptability against stresses, leading to neurodegenerative disorders.
[Show abstract][Hide abstract]ABSTRACT: DJ-1 is an antioxidant protein whose loss of function by gene mutations has been linked to familial Parkinson’s disease (PD). The main objective of the present study was to determine if this molecule was also involved in the pathogenesis of sporadic PD. For this purpose, quantitative immunoblot assays were performed to evaluate DJ-1 in cerebrospinal fluids (CSF) collected from sporadic PD patients (n=40) and non-PD controls (n=38). The results showed that the CSF DJ-1 levels in PD were significantly higher than those in non-PD controls. Especially, upregulation of CSF DJ-1 in the early stage of PD (Yahr I–II) were distinct compared to those in the advanced stage of PD (Yahr III–IV) and non-PD controls (p
Article · Jul 2006 · Biochemical and Biophysical Research Communications