Establishment of Primary Culture Models of Multiple System Atrophy Based on Expression of a-Synuclein in Oligodendrocytes

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
oligodendrocytes 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.