Pathogenesis of multiple system atrophy

Multiple 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 alpha-synuclein (alpha SYN)- 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 aSYN 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 etio-pathological 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 aSYN accumulation in oligodendrocytes can secondarily lead to neuronal cell death.