Pathogenesis Of Multiple System Atrophy Research Articles

Involvement of Peripheral Nerves in the Transgenic PLP-α-Syn Model of Multiple System Atrophy: Extending the Phenotype.

Multiple system atrophy (MSA) is a fatal, rapidly progressive neurodegenerative disease with (oligodendro-)glial cytoplasmic α-synuclein (α-syn) inclusions (GCIs). Peripheral neuropathies have been reported in up to 40% of MSA patients, the cause remaining unclear. In a transgenic MSA mouse model featuring GCI-like inclusion pathology based on PLP-promoter driven overexpression of human α-syn in oligodendroglia motor and non-motor deficits are associated with MSA-like neurodegeneration. Since α-syn is also expressed in Schwann cells we aimed to investigate whether peripheral nerves are anatomically and functionally affected in the PLP-α-syn MSA mouse model.ResultsTo this end, heat/cold as well as mechanical sensitivity tests were performed. Furthermore, in vivo and ex vivo nerve conduction and the G-ratios of the sciatic nerve were analyzed, and thermosensitive ion channel mRNA expression in dorsal root ganglia (DRG) was assessed. The presence of human α-syn in Schwann cells was associated with subtle behavioral impairments. The G-ratio of the sciatic nerve, the conduction velocity of myelinated and unmyelinated primary afferents and the expression of thermosensitive ion channels in the sensory neurons, however, were similar to wildtype mice.ConclusionOur results suggest that the PNS appears to be affected by Schwann cell α-syn deposits in the PLP-α-syn MSA mouse model. However, there was no consistent evidence for functional PNS perturbations resulting from such α-syn aggregates suggesting a more central cause of the observed behavioral abnormalities. Nonetheless, our results do not exclude a causal role of α-syn in the pathogenesis of MSA associated peripheral neuropathy.

Contra-Directional Expression of Serum Homocysteine and Uric Acid as Important Biomarkers of Multiple System Atrophy Severity: A Cross-Sectional Study.

Serum Hcy was higher in MSA patients when compared to healthy subjects, particularly in male patients.Serum UA was lower in MSA patients when compared healthy subjects, particularly in male patients.Serum Hcy levels were significantly positively correlated with the severity of MSA.The ROC curve for the combination of Hcy and UA showed potential diagnostic value in discriminating MSA from healthy subjects. There is evidence suggesting that inflammatory responses play a critical role in the pathogenesis of multiple system atrophy (MSA). Whether inflammatory mediators can be used as reliable biomarkers to detect the severity and progression of MSA remains largely unknown. We performed a cross-sectional study that included 47 patients with MSA and 50 healthy age-matched controls. Serum levels of homocysteine (Hcy), uric acid (UA), and C-reactive protein (CRP) were measured. These levels positively correlated with the severity of MSA, based on both motor and non-motor symptoms. Several scales were used to rate the severity of MSA, including the Unified multiple system atrophy rating scale, Parkinson's disease sleep scale, Non-motor Symptoms Scale, the Schwab & England activities of daily living scale, Webster Scale, modified Hoehn and Yahr staging scale, and the Mini-Mental State Examination. Receiver operating characteristic (ROC) curves was applied to map the diagnostic accuracy of MSA against healthy subjects. Compared with healthy subjects, we found that serum Hcy was higher, UA was lower, and CRP levels were unchanged in MSA patients. These findings were especially prominent in male patients. No significant differences of serum Hcy and UA were observed between patients of MSA and PD. Interestingly, there was a significant correlation between Hcy levels and MSA severity such as movement dysfunction, declined cognition, and cardiovascular symptoms. Additionally, the ROC curve for the combination of Hcy and UA (AUC 0.736) showed potential diagnostic value in discriminating MSA from healthy subjects. Our findings suggest that the inflammatory mediators Hcy and UA may play important roles in the pathogenesis of MSA. The measurement of serum Hcy and UA levels could then be a useful tool to accurately distinguish MSA from healthy subjects.

Pathogenesis of Multiple System Atrophy - Recent Developments

Multiple System Atrophy (MSA) is a rare adult-onset neurodegenerative disorder of uncertain etiology, clinically manifesting with parkinsonism, cerebellar impairment, autonomic dysfunction and pyramidal signs. The pathological process affects striatonigral, olivopontocerebellar, and autonomic nervous systems. The major clinical variants correlate to the morphologic phenotypes of striatonigral degeneration (MSA-P) and olivopontocerebellar atrophy (MSA-C). Pathologically, MSA is characterized by Glial Cytoplasmic Inclusions (GCIs) and Neuronal Inclusions (NIs) containing abnormal filamentous α-synuclein that involve many areas of the nervous system. In addition to extopic deposition of modified α-synuclein in oligodendroglia and neurons, oxidative stress, proteasomal and mitochondrial dysfunction, dysregulation of myelin lipids, demyelination, neuroinflammation, and energy failure contribute to the pathogenesis of system-specific neurodegeneration in this unique proteinopathy.

Association of the COQ2 V393A Variant with Parkinson's Disease: A Case-Control Study and Meta-Analysis.

Both Parkinson’s disease (PD) and multiple system atrophy (MSA) are neurodegenerative diseases of uncertain etiology, but they show similarities in their pathology and clinical course. The fact that the gene encoding α-synuclein is associated with both diseases also suggests that they share some genetic determinants. Recent studies in Japan associating MSA with a variant in the COQ2 gene led us to question whether variants in the COQ2 gene are associated with PD in Han Chinese in a case-control study. A total of 564 patients with PD were genotyped using the ligase detection rection, together with 484 gender- and age-matched healthy subjects. The M128V and R387X variants of COQ2 were not detected in patients or controls; instead, we detected only the heterozygous V393A variant (CT genotype). The frequency of the CT genotype encoding the V393A mutation was significantly higher in patients PD (4.08%) than in controls (1.86%), corresponding to an odds ratio of 2.24 (95%CI 1.03 to 4.90, p = 0.037). The frequency of the C allele of the V393A variant was significantly higher in patients with PD than in controls (OR 2.22, 95%CI 1.02 to 4.82, p = 0.039), and this was also observed in a meta-analysis of studies from mainland China, Taiwan and Japan. Subgroup analysis of our data showed that the V393A variant was significantly associated with early-onset PD (OR 3.71, 95%CI 1.51 to 9.15, p = 0.002) but not with late-onset disease (OR 1.65, 95%CI 0.69 to 3.95, p = 0.260). Gender was not significantly associated with either genotype or minor allele frequencies. In conclusion, our findings show for the first time that the V393A variant in the COQ2 gene increases risk of PD among the population of east Asia. These results, combined with research on Japanese, lend genetic support to the hypothesis that oxidative stress underlies pathogenesis of both PD and MSA.

Advance in genetic research on multiple system atrophy

Multiple system atrophy (MSA) is a progressive neurodegenerative disorder. Widespread presence of glial cytoplasmic inclusions is the neuropathologic hallmark of MSA. The disease has long been considered as a sporadic disorder. However, in recent years, a few familial cases of MSA have been reported, and researches have verified certain genetic variants could increase the risk of MSA. These indicated genetic factors may play an imported role in the pathogenesis of MSA. In this review, the emerging evidence in favor of genetic players in MSA is discussed.

Promoting oligodendrocyte progenitor cell maturation and remyelination as a novel therapeutical approach for multiple system atrophy

Alpha-synuclein (aSyn) aggregation within mature oligodendrocytes is the characteristic neuropathological feature of multiple system atrophy (MSA). In fact, dysfunction of oligodendrocytes is considered as a primary event in MSA pathogenesis leading to myelin loss and, ultimately, reduced axonal integrity and neuronal cell loss. Oligodendrocyte progenitor cells (OPCs) are widely distributed in the adult central nervous system and represent a potential endogenous source for replacement of such dysfunctional oligodendrocytes. The extent to which OPCs are affected in MSA or even contribute to MSA pathogenesis remains undefined. Thus, we analyzed OPCs post-mortem in MSA brains and in a pre-clinical MSA mouse model expressing aSyn under the myelin basic protein (MBP) promoter. Importantly, we detected elevated numbers of striatal OPCs in MSA and its model 1 . Observing aSyn-positive OPCs in MSA patients, we additionally established two independent in vitro models in order to explore the effect of intracellular aSyn on OPC maturation. Both stable aSyn expressing OPC-like central glia-4 (CG4) cells 1 and transiently aSyn expressing primary OPCs derived from neonatal rats 2 robustly showed a severely reduced maturation. Similarly, primary OPCs exhibit a delayed maturation upon uptake of recombinant aSyn 2 . Taken together, our findings indicate that OPC dysfunction is a pathological feature of MSA. In addition, promoting OPC differentiation may represent a novel and promising interventional strategy for therapeutic approaches in MSA.

Exploring myelin dysfunction in multiple system atrophy.

Multiple system atrophy (MSA) is a rare, yet fatal neurodegenerative disease that presents clinically with autonomic failure in combination with parkinsonism or cerebellar ataxia. MSA impacts on the autonomic nervous system affecting blood pressure, heart rate and bladder function, and the motor system affecting balance and muscle movement. The cause of MSA is unknown, no definitive risk factors have been identified, and there is no cure or effective treatment. The definitive pathology of MSA is the presence of α-synuclein aggregates in the brain and therefore MSA is classified as an α-synucleinopathy, together with Parkinson's disease and dementia with Lewy bodies. Although the molecular mechanisms of misfolding, fibrillation and aggregation of α-synuclein partly overlap with other α-synucleinopathies, the pathological pathway of MSA is unique in that the principal site for α-synuclein deposition is in the oligodendrocytes rather than the neurons. The sequence of pathological events of MSA is now recognized as abnormal protein redistributions in oligodendrocytes first, followed by myelin dysfunction and then neurodegeneration. Oligodendrocytes are responsible for the production and maintenance of myelin, the specialized lipid membrane that encases the axons of all neurons in the brain. Myelin is composed of lipids and two prominent proteins, myelin basic protein and proteolipid protein. In vitro studies suggest that aberration in protein distribution and lipid transport may lead to myelin dysfunction in MSA. The purpose of this perspective is to bring together available evidence to explore the potential role of α-synuclein, myelin protein dysfunction, lipid dyshomeostasis and ABCA8 in MSA pathogenesis.

Transcriptome analysis of grey and white matter cortical tissue in multiple system atrophy.

Multiple system atrophy (MSA) is a distinct member of a group of neurodegenerative diseases known as α-synucleinopathies, which are characterized by the presence of aggregated α-synuclein in the brain. MSA is unique in that the principal site for α-synuclein deposition is in the oligodendrocytes rather than neurons. The cause of MSA is unknown, and the pathogenesis of MSA is still largely speculative. Brain transcriptome perturbations during the onset and progression of MSA are mostly unknown. Using RNA sequencing, we performed a comparative transcriptome profiling analysis of the grey matter (GM) and white matter (WM) of the frontal cortex of MSA and control brains. The transcriptome sequencing revealed increased expression of the alpha and beta haemoglobin genes in MSA WM, decreased expression of the transthyretin (TTR) gene in MSA GM and numerous region-specific long intervening non-coding RNAs (lincRNAs). In contrast, we observed only moderate changes in the expression patterns of the α-synuclein (SNCA) gene, which confirmed previous observations by other research groups. Our study suggests that at the transcriptional level, MSA pathology may be related to increased iron levels in WM and perturbations of the non-coding fraction of the transcriptome.

Altered lipid levels provide evidence for myelin dysfunction in multiple system atrophy.

Multiple system atrophy (MSA) is a rapidly-progressive neurodegenerative disease characterized by parkinsonism, cerebellar ataxia and autonomic failure. A pathological hallmark of MSA is the presence of α-synuclein deposits in oligodendrocytes, the myelin-producing support cells of the brain. Brain pathology and in vitro studies indicate that myelin instability may be an early event in the pathogenesis of MSA. Lipid is a major constituent (78% w/w) of myelin and has been implicated in myelin dysfunction in MSA. However, changes, if any, in lipid level/distribution in MSA brain are unknown. Here, we undertook a comprehensive analysis of MSA myelin. We quantitatively measured three groups of lipids, sphingomyelin, sulfatide and galactosylceramide, which are all important in myelin integrity and function, in affected (under the motor cortex) and unaffected (under the visual cortex) white matter regions. For all three groups of lipids, most of the species were severely decreased (40–69%) in affected but not unaffected MSA white matter. An analysis of the distribution of lipid species showed no significant shift in fatty acid chain length/content with MSA. The decrease in lipid levels was concomitant with increased α-synuclein expression. These data indicate that the absolute levels, and not distribution, of myelin lipids are altered in MSA, and provide evidence for myelin lipid dysfunction in MSA pathology. We propose that dysregulation of myelin lipids in the course of MSA pathogenesis may trigger myelin instability.

Neuropathology of multiple system atrophy: new thoughts about pathogenesis.

Multiple system atrophy (MSA) is a fatal adult-onset neurodegenerative disorder of uncertain etiology, clinically manifesting with autonomic failure associated with parkinsonism, cerebellar dysfunction, and pyramidal signs in variable combination. The pathological process affects central autonomic, striatonigral, and olivopontocerebellar systems. These show varying degrees of neurodegeneration and underlie the stratification of the heterogenous disorder into MSA-P and MSA-C clinical variants, which correlate to the morphologic phenotypes of striatonigral degeneration and olivopontocerebellar atrophy (MSA-C). The lesions are not limited to these most consistently and severely affected systems but may involve many other parts of the central, peripheral, and autonomic nervous systems, underpinning the multisystem character of MSA. The histological core feature are glial cytoplasmic inclusions (GCIs, Papp-Lantos bodies) in all types of oligodendroglia that contain aggregates of misfolded α-Synuclein (α-Syn). In addition to the ectopic appearance of α-Syn in oligodendrocytes and other cells, oxidative stress, proteasomal and mitochondrial dysfunction, excitotoxiciy, neuroinflammation, metabolic changes, and energy failure are important contributors to the pathogenesis of MSA, as shown by various neurotoxic and transgenic animal models. Although the basic mechanisms of α-Syn-triggered neurodegeneration are not completely understood, neuron-to-oligodendrocyte transfer of α-Syn by prion-like spreading, inducing oligodendroglial and myelin dysfunction associated with chronic neuroinflammation, are suggested finally to lead to a system-specific pattern of neurodegeneration.

Altered expression of miR-202 in cerebellum of multiple-system atrophy.

Cerebellar degeneration is a devastating manifestation of cerebellar-type multiple-system atrophy (MSA), a rapidly progressive neurodegenerative disease, and the exact pathogenesis is unknown. Here, we examined the expression of micro-RNAs (miRNAs), which are short noncoding RNAs, in the cerebellum of MSA and the key target genes. miRNA microarray found 11 miRNAs with significantly different expression in MSA cerebellum compared to cerebellum from age-, sex-, and postmortem interval-matched controls. miR-202 was the most upregulated in the MSA samples. In silico analysis, followed by target gene luciferase assay, in vitro transfection, and Western blotting in human samples showed that miR-202 downregulates Oct1 (Pou2f1), a transcription factor expressed in cerebellar Purkinje cells. Transfection of Neuro-2a cells with miR-202 enhanced oxidative stress-induced cell death, and an antagomir to miR-202 inhibited this effect of miR-202. This study provides novel insight into the role of miRNA in cerebellar degeneration and suggests that miR-202 is a key miRNA mediating the pathogenesis of MSA.

Lipid dysfunction and pathogenesis of multiple system atrophy

Multiple system atrophy (MSA) is a progressive neurodegenerative disease characterized by the accumulation of α-synuclein protein in the cytoplasm of oligodendrocytes, the myelin-producing support cells of the central nervous system (CNS). The brain is the most lipid-rich organ in the body and disordered metabolism of various lipid constituents is increasingly recognized as an important factor in the pathogenesis of several neurodegenerative diseases. α-Synuclein is a 17 kDa protein with a close association to lipid membranes and biosynthetic processes in the CNS, yet its precise function is a matter of speculation, particularly in oligodendrocytes. α-Synuclein aggregation in neurons is a well-characterized feature of Parkinson’s disease and dementia with Lewy bodies. Epidemiological evidence and in vitro studies of α-synuclein molecular dynamics suggest that disordered lipid homeostasis may play a role in the pathogenesis of α-synuclein aggregation. However, MSA is distinct from other α-synucleinopathies in a number of respects, not least the disparate cellular focus of α-synuclein pathology. The recent identification of causal mutations and polymorphisms in COQ2, a gene encoding a biosynthetic enzyme for the production of the lipid-soluble electron carrier coenzyme Q10 (ubiquinone), puts membrane transporters as central to MSA pathogenesis, although how such transporters are involved in the early myelin degeneration observed in MSA remains unclear. The purpose of this review is to bring together available evidence to explore the potential role of membrane transporters and lipid dyshomeostasis in the pathogenesis of α-synuclein aggregation in MSA. We hypothesize that dysregulation of the specialized lipid metabolism involved in myelin synthesis and maintenance by oligodendrocytes underlies the unique neuropathology of MSA.

Altered lipid levels provide evidence for myelin dysfunction in multiple system atrophy

Multiple system atrophy (MSA) is a rapidly-progressive neurodegenerative disease characterized by parkinsonism, cerebellar ataxia and autonomic failure. A pathological hallmark of MSA is the presence of α-synuclein deposits in oligodendrocytes, the myelin-producing support cells of the brain. Brain pathology and in vitro studies indicate that myelin instability may be an early event in the pathogenesis of MSA. Lipid is a major constituent (78% w/w) of myelin and has been implicated in myelin dysfunction in MSA. However, changes, if any, in lipid level/distribution in MSA brain are unknown. Here, we undertook a comprehensive analysis of MSA myelin. We quantitatively measured three groups of lipids, sphingomyelin, sulfatide and galactosylceramide, which are all important in myelin integrity and function, in affected (under the motor cortex) and unaffected (under the visual cortex) white matter regions. For all three groups of lipids, most of the species were severely decreased (40–69%) in affected but not unaffected MSA white matter. An analysis of the distribution of lipid species showed no significant shift in fatty acid chain length/content with MSA. The decrease in lipid levels was concomitant with increased α-synuclein expression. These data indicate that the absolute levels, and not distribution, of myelin lipids are altered in MSA, and provide evidence for myelin lipid dysfunction in MSA pathology. We propose that dysregulation of myelin lipids in the course of MSA pathogenesis may trigger myelin instability.

Susceptibility gene in multiple system atrophy (MSA)

To elucidate molecular bases of multiple system atrophy (MSA), we first focused on recently identified MSA multiplex families. Though linkage analyses followed by whole genome resequencing, we have identified a causative gene, COQ2, for MSA. We then conducted comprehensive nucleotide sequence analysis of COQ2 of sporadic MSA cases and controls, and found that functionally deleterious COQ2 variants confer a strong risk for developing MSA. COQ2 encodes an enzyme in the biosynthetic pathway of coenzyme Q10. Decreased synthesis of coenzyme Q10 is considered to be involved in the pathogenesis of MSA through decreased electron transport in mitochondria and increased vulnerability to oxidative stress.

XIAP immunoreactivity in glial and neuronal cytoplasmic inclusions in multiple system atrophy

X-linked inhibitor of apoptosis protein (XIAP) selectively binds to caspases-3, -7 and -9, and inhibits the activities of these caspases. To elucidate the role of XIAP in patients with multiple system atrophy (MSA), we performed immunohistochemical studies on XIAP in formalin-fixed, paraffin-embedded sections from 8 normal subjects and 10 patients with MSA. In normal brains, several types of neurons were immunostained for XIAP, and XIAP-immunopositive oligodendrocytes were scattered throughout the cerebral and cerebellar white matter. In the MSA brains, neuronal XIAP immunoreactivity was spared even in the severely-affected lesions, and glial cytoplasmic inclusions (GCIs), neuronal cytoplasmic inclusions (NCIs) and dystrophic neurites were all intensely immunoreactive for XIAP. A semiquantitative analysis of mid-pons sections double-immunostained for XIAP and α-synuclein demonstrated that the average percentages of XIAP-immunopositive GCIs and NCIs in the pontine nucleus were 70.2% and 82.2%, respectively. Our results suggest that a widespread accumulation of XIAP may occur in brains with MSA, and that XIAP may be partially associated with the pathogenesis of MSA.

Alpha‐synuclein transfers from neurons to oligodendrocytes

The origin of α-synuclein (α-syn)-positive glial cytoplasmic inclusions found in oligodendrocytes in multiple system atrophy (MSA) is enigmatic, given the fact that oligodendrocytes do not express α-syn mRNA. Recently, neuron-to-neuron transfer of α-syn was suggested to contribute to the pathogenesis of Parkinson's disease. In this study, we explored whether a similar transfer of α-syn might occur from neurons to oligodendrocytes, which conceivably could explain how glial cytoplasmic inclusions are formed. We studied oligodendrocytes in vitro and in vivo and examined their ability to take up different α-syn assemblies. First, we treated oligodendrocytes with monomeric, oligomeric, and fibrillar forms of α-syn proteins and investigated whether α-syn uptake is dynamin-dependent. Second, we injected the same α-syn species into the mouse cortex to assess their uptake in vivo. Finally, we monitored the presence of human α-syn within rat oligodendroglial cells grafted in the striatum of hosts displaying Adeno-Associated Virus-mediated overexpression of human α-syn in the nigro-striatal pathway. Here, we show that oligodendrocytes take up recombinant α-syn monomers, oligomers and, to a lesser extent, fibrils in vitro in a concentration and time-dependent manner, and that this process is inhibited by dynasore. Further, we demonstrate in our injection model that oligodendrocytes also internalize α-syn in vivo. Finally, we provide the first direct evidence that α-syn can transfer to grafted oligodendroglial cells from host rat brain neurons overexpressing human α-syn. Our findings support the hypothesis of a neuron-to-oligodendrocyte transfer of α-syn, a mechanism that may play a crucial role in the progression and pathogenesis of MSA.

Serum lipid levels are associated with the prevalence but not with the disease progression of multiple system atrophy in a Chinese population

Objectives: Alpha-synuclein is involved in the pathogenesis of multiple system atrophy (MSA) and can be regulated by lipids. This study aims to validate the correlation between lipid levels and the prevalence of MSA as well as its progression.Methods: A total of 234 patients with probable MSA and 240 age- and gender-matched healthy controls were included in this study. Lipid contents, including total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG), were evaluated. The unified MSA rating scale (UMSARS) was used to assess the severity of MSA.Results: Lipid levels in MSA patients were significantly lower than those in healthy controls. Patients with MSA-C were significantly younger, had higher body mass indices (BMIs), higher UMSARS scores, and lower HDL-C contents compared with MSA-P patients. Subjects with the lowest quartiles and the second quartiles of total cholesterol, LDL-C, and HDL-C had high prevalence of MSA compared with subjects with the highest quartiles. No correlation was found between the mean rate of annualized changes and serum levels of lipids as well as other independent factors, such as age, BMI, gender, subtypes (C-type or P-type), and disease duration at the initial visit, in 107 followed-up MSA patients.Discussion: Low levels of total cholesterol, LDL-C, HDL-C, and TG increased the prevalence of MSA in a Chinese population. Patients with MSA-C showed significantly lower levels of HDL-C than MSA-P patients. However, lipids did not deteriorate or improve the progression of MSA.

Widespread microRNA dysregulation in multiple system atrophy - disease-related alteration in miR-96.

MicroRNA (miRNA) are short sequences of RNA that function as post-transcriptional regulators by binding to target mRNA transcripts resulting in translational repression. A number of recent studies have identified miRNA as being involved in neurodegenerative disorders including Alzheimer's disease, Parkinson's disease and Huntington's disease. However, the role of miRNA in multiple system atrophy (MSA), a progressive neurodegenerative disorder characterized by oligodendroglial accumulation of alpha-synuclein remains unexamined. In this context, this study examined miRNA profiles in MSA cases compared with controls and in transgenic (tg) models of MSA compared with non-tg mice. The results demonstrate a widespread dysregulation of miRNA in MSA cases, which is recapitulated in the murine models. The study employed a cross-disease, cross-species approach to identify miRNA that were either specifically dysregulated in MSA or were commonly dysregulated in neurodegenerative conditions such as Alzheimer's disease, dementia with Lewy bodies, progressive supranuclear palsy and corticobasal degeneration or the tg mouse model equivalents of these disorders. Using this approach we identified a number of miRNA that were commonly dysregulated between disorders and those that were disease-specific. Moreover, we identified miR-96 as being up-regulated in MSA. Consistent with the up-regulation of miR-96, mRNA and protein levels of members of the solute carrier protein family SLC1A1 and SLC6A6, miR-96 target genes, were down-regulated in MSA cases and a tg model of MSA. These results suggest that miR-96 dysregulation may play a role in MSA and its target genes may be involved in the pathogenesis of MSA.

Pathogenesis of multiple system atrophy

AbstractMultiple system atrophy (MSA) is an adult‐onset, progressive neurodegenerative disease involving parkinsonism, ataxia, and autonomic failure, in any combination. The unifying histopathological hallmark of MSA is the appearance of α‐synuclein (αSYN)‐positive, triangular‐shaped glial cytoplasmic inclusion (GCI) in affected brain regions including striatonigral and/or olivopontocerebellar systems. It is known that GCI follows the regions showing neuronal loss and gliosis, and the incidence of GCI is well correlated with disease severity and duration, suggesting that the oligodendroglial αSYN pathology in MSA would be a prerequisite for the disease rather than a consequence of glio‐neuronal degeneration. The mechanisms underlying the neuronal cell loss followed by oligodendroglial degeneration in MSA still remain elusive; however, recent observations from cultured cells, animal models, neuropathological and genetic studies have highlighted the several etiopathological factors including mitochondrial dysfunction, oxidative stress, aberrant misfolded protein processing and neuroinflammation. In the present review, we summarize a general overview of potential pathogenic processes and discuss the topics for debate especially focusing on the mechanisms by which αSYN accumulation in oligodendrocytes can secondarily lead to neuronal cell death.

Uric acid is associated with the prevalence but not disease progression of multiple system atrophy in Chinese population

Oxidative stress is involved in the pathogenesis of multiple system atrophy (MSA). Uric acid has an antioxidative effect. Our aim is to clarify the correlations between serum uric acid and MSA in Chinese population. A total of 234 patients with probable MSA and 240 age- and gender- matched healthy controls were included in the study. The serum uric acid levels of all the patients and controls were evaluated. The Unified MSA Rating Scale (UMSARS) was used to assess the severity and the mean rate of annualized changes of UMSARS to assess the progression of MSA. The mean age of MSA patients was 58.90 ± 9.00 years and the mean disease duration was 2.60 ± 1.75 years. The serum uric acid levels of MSA patients were significantly lower than that of controls in males (p = 0.0001). The occurrence of MSA was increased in the lowest uric acid quartiles compared with the highest uric acid quartiles (p = 0.005). In a gender-specific analysis, increased occurrence was found in the lowest quartiles and second quartiles compared with the highest quartiles in males (p = 0.001 and p = 0.0001 respectively), but not in females. No correlation was found between the mean rate of annualized changes and serum levels of uric acid, as well as other independent factors, such as age, BMI, gender, subtype (C-type or P-type) and disease duration at the initial visit in 107 followed-up patients. MSA patients have lower levels of serum uric acid than controls. High levels of serum uric acid may be associated with a lower prevalence of MSA in the Chinese population, especially in males. However, serum uric acid does not deteriorate or ameliorate the progression of MSA.