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

Fillon, Gwenaelle (2005): Establishment of Primary Culture Models of Multiple System Atrophy Based on Expression of a-Synuclein in Oligodendrocytes: Analysis of a-Synuclein Aggregation and Associated Pathologies. Dissertation, LMU München: Fakultät für Biologie

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.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Keywords: Multiple System Atrophy, glial cytoplasmic inclusion, a-synuclein, oligodendrocyte, apoptosis, proteasome, cell culture model
• Themengebiete: 500 Naturwissenschaften und Mathematik ; 500 Naturwissenschaften und Mathematik > 570 Biowissenschaften, Biologie
• Fakultäten: Fakultät für Biologie
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 19. September 2005
• 1. Bericht­erstatter:in: Cremer, Thomas