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

Abstract

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.

• Item Type: Thesis (Dissertation, LMU Munich)
• Keywords: Multiple System Atrophy, glial cytoplasmic inclusion, a-synuclein, oligodendrocyte, apoptosis, proteasome, cell culture model
• Dewey Decimal Classification: 600 Natural sciences and mathematics; 600 Natural sciences and mathematics > 570 Life sciences
• Faculties: Faculty of Biology
• Language: English
• Date Accepted: 19. September 2005
• 1. Referee: Cremer, Thomas
• Persistent Identifier (URN): urn:nbn:de:bvb:19-129297
• Signature of the printed copy: 0001/UMC19373