Systemic proteasome inhibition triggers neurodegeneration in a transgenic mouse model expressing human α-synuclein under oligodendrocyte promoter: implications for multiple system atrophy

Multiple system atrophy (MSA) is a progressive late onset neurodegenerative alpha-synucleinopathy with unclear pathogenesis. Recent genetic and pathological studies support a central role of alpha-synuclein (alpha SYN) in MSA pathogenesis. Oligodendroglial cytoplasmic inclusions of fibrillar alpha SYN and dysfunction of the ubiquitin-proteasome system are suggestive of proteolytic stress in this disorder. To address the possible pathogenic role of oligodendroglial alpha SYN accumulation and proteolytic failure in MSA we applied systemic proteasome inhibition (PSI) in transgenic mice with oligodendroglial human alpha SYN 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 alpha SYN 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 alpha SYN mice. In contrast no neurodegeneration was detected in PSI-treated wild-type controls. PSI treatment of transgenic alpha SYN mice was associated with significant ultrastructural alterations including accumulation of fibrillar human alpha SYN 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.