Abstract
Multiple system atrophy (MSA) is a progressive late onset neurodegenerative α-synucleinopathy with unclear pathogenesis. Recent genetic and pathological studies support a central role of α-synuclein (αSYN) in MSA pathogenesis. Oligodendroglial cytoplasmic inclusions of fibrillar αSYN and dysfunction of the ubiquitin–proteasome system are suggestive of proteolytic stress in this disorder. To address the possible pathogenic role of oligodendroglial αSYN accumulation and proteolytic failure in MSA we applied systemic proteasome inhibition (PSI) in transgenic mice with oligodendroglial human αSYN expression and determined the presence of MSA-like neurodegeneration in this model as compared to wild-type mice. PSI induced open field motor disability in transgenic αSYN mice but not in wild-type mice. The motor phenotype corresponded to progressive and selective neuronal loss in the striatonigral and olivopontocerebellar systems of PSI-treated transgenic αSYN mice. In contrast no neurodegeneration was detected in PSI-treated wild-type controls. PSI treatment of transgenic αSYN mice was associated with significant ultrastructural alterations including accumulation of fibrillar human αSYN in the cytoplasm of oligodendroglia, which resulted in myelin disruption and demyelination characterized by increased g-ratio. The oligodendroglial and myelin pathology was accompanied by axonal degeneration evidenced by signs of mitochondrial stress and dysfunctional axonal transport in the affected neurites. In summary, we provide new evidence supporting a primary role of proteolytic failure and suggesting a neurodegenerative pathomechanism related to disturbed oligodendroglial/myelin trophic support in the pathogenesis of MSA.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-012-0977-5) contains supplementary material, which is available to authorized users.
Highlights
Multiple system atrophy (MSA) is a sporadic neurodegenerative disorder clinically characterized by parkinsonism, cerebellar, autonomic, and pyramidal dysfunction [37]
Open field analysis detected no effect of proteasome inhibition (PSI) treatment in wild-type mice, but showed motor disability measured by reduction of the horizontal activity of PSItreated compared to vehicle-treated proteolipid protein (PLP)-human aSYN (haSYN) transgenic mice 2 weeks after treatment, which was still observed 12 weeks after treatment (Fig. 1a)
The current study provides experimental evidence for possible mechanisms of progressive MSA-like neurodegeneration resulting from enhanced proteolytic stress related to systemic proteasome inhibition and oligodendroglial a-synucleinopathy
Summary
Multiple system atrophy (MSA) is a sporadic neurodegenerative disorder clinically characterized by parkinsonism, cerebellar, autonomic, and pyramidal dysfunction [37]. Recent evidence indicates that dysfunction of the ubiquitin–proteasome system (UPS) is a common pathogenic mechanism in a-synucleinopathies including Parkinson’s disease (PD), dementia with Lewy bodies, and MSA [5]. In MSA brain tissue reduced immunoreactivity for the 20S-a subunit of the core proteasome complex has been shown in dopaminergic nigral neurons [5]. The 20S proteasome subunit gene expression has been found to be downregulated in the pons of MSA patients [20]. These data suggest that proteolytic stress in MSA might result from impaired degradation (proteasome dysfunction) and excess aberrant accumulation of aSYN affecting oligodendroglia by yet unknown mechanisms, which eventually lead to selective and wide-spread multisystem neurodegeneration
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