FAS-dependent cell death in α-synuclein transgenic oligodendrocyte models of multiple system atrophy

Multiple system atrophy is a parkinsonian neurodegenerative disorder. It is cytopathologically characterized by accumulation of the protein p25α in cell bodies of oligodendrocytes followed by accumulation of aggregated α-synuclein in so-called glial cytoplasmic inclusions. p25α is a stimulator of α-synuclein aggregation, and coexpression of α-synuclein and p25α in the oligodendroglial OLN-t40-AS cell line causes α-synuclein aggregate-dependent toxicity. In this study, we investigated whether the FAS system is involved in α-synuclein aggregate dependent degeneration in oligodendrocytes and may play a role in multiple system atrophy. Using rat oligodendroglial OLN-t40-AS cells we demonstrate that the cytotoxicity caused by coexpressing α-synuclein and p25α relies on stimulation of the death domain receptor FAS and caspase-8 activation. Using primary oligodendrocytes derived from PLP-α-synuclein transgenic mice we demonstrate that they exist in a sensitized state expressing pro-apoptotic FAS receptor, which makes them sensitive to FAS ligand-mediated apoptosis. Immunoblot analysis shows an increase in FAS in brain extracts from multiple system atrophy cases. Immunohistochemical analysis demonstrated enhanced FAS expression in multiple system atrophy brains notably in oligodendrocytes harboring the earliest stages of glial cytoplasmic inclusion formation. Oligodendroglial FAS expression is an early hallmark of oligodendroglial pathology in multiple system atrophy that mechanistically may be coupled to α-synuclein dependent degeneration and thus represent a potential target for protective intervention.
This work was supported by the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement n° 241791 (MEFOPA), n° 238316 (Neurasync), the Lundbeck Foundation, the Deutsche Forschungsgemeinschaft (SFB 596, project A1), the European consortium to develop PD gene therapy (NEUROPARK), the Fondation pour la Recherche Médicale, The Danish Medical Research Council, Aarhus University, the Foundation of 1984 for treatment of Parkinson disease, Federal Ministry of Education and Research (Project-No. 01GI0299). GMH and WPG have NHMRC Research Fellowships (630434 & 535014). Human brain samples were received thanks to support from the National Health and Medical Research Council of Australia (NHMRC), Neuroscience Research Australia, the University of New South Wales, the Schizophrenia Research Institute, the National Institute of Alcohol Abuse and Alcoholism (NIH (NIAAA) R24AA012725, University of Sydney and the Flinders Medical Centre Foundation.