Multiple system atrophy (MSA) is a neurodegenerative syndrome characterized by (oligodendro)glial cytoplasmic inclusions (GCIs) composed of a-synuclein. I have developed cell culture models of MSA based on overexpression of human a-synuclein in primary mouse oligodendrocytes. In oligodendrocytes derived from (PLP)-a-synuclein transgenic mice, elevation of a-synuclein levels by proteasome inhibition induced GCI formation and enhanced apoptosis. The same effects were observed in wild-type

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... ndrocytes transduced with a lentiviral vector encoding a-synuclein. In contrast, lenti-a-synuclein failed to yield inclusions, and even prevented aggregation and cytotoxicity of a-synuclein. Selective caspase inhibitors blocking the intrinsic (mitochondrial) apoptosis pathway and the extrinsic pathway reduced aSYN-mediated oligodendrocyte cell death. a-synuclein overexpressing oligodendrocytes strongly expressed the pro-apoptotic Fas receptor and were specifically sensitized to Fas-mediated apoptosis. In MSA brain, Fas was expressed on oligodendrocytes with GCIs. Thus, induction of a-synuclein leads to GCI formation and may contribute to oligodendrocyte dysfunction and cell death in MSA.