GLIAL CYTOPLASMIC INCLUSIONS IN WHITE-MATTER OLIGODENDROCYTES OF MULTIPLE SYSTEM ATROPHY BRAINS CONTAIN INSOLUBLE ALPHA-SYNUCLEIN

Recently, alpha-synuclein was shown to be a structural component of th e filaments in Lewy bodies (LBs) of Parkinson's disease (PD), dementia with LBs (DLB) as well as the LB variant of Alzheimer's disease, and this suggests that alpha-synuclein could play a mechanistic role in th e pathogenesis of these disorders. To determine whether alpha-synuclei n is a building block of inclusions in other neurodegenerative movemen t disorders, we examined brains from patients with multiple system atr ophy (MSA) and detected alpha-synuclein, but not beta- or gamma-synucl ein, in glial cytoplasmic inclusions (GCIs) throughout the MSA brain. In MSA white matter, alpha-synudein-positive GCIs were restricted to o ligodendrocytes, and alpha-synuclein was localized to the filaments in GCIs by immunoelectron microscopy. Finally, we demonstrated that inso luble alpha-synuclein accumulated selectively in MSA white matter with alpha-synuclein-positive GCIs. Taken together with evidence that LBs contain insoluble alpha-synuclein, our data suggest that a reduction i n the solubility of alpha-synuclein may induce this protein to form fi laments that aggregate into cytoplasmic inclusions, which contribute t o the dysfunction or death of glial cells as well as neurons in neurod egenerative disorders with different phenotypes.