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

• Published in: PloS one Vol. 8; no. 1; p. e55243
• Main Authors: Kragh, Christine L, Fillon, Gwenaëlle, Gysbers, Amanda, Hansen, Hanne D, Neumann, Manuela, Richter-Landsberg, Christiane, Haass, Christian, Zalc, Bernard, Lubetzki, Catherine, Gai, Wei-Ping, Halliday, Glenda M, Kahle, Philipp J, Jensen, Poul H
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 25.01.2013; Public Library of Science (PLoS)
• Subjects: Accumulation; Aged; alpha-Synuclein - genetics; alpha-Synuclein - metabolism; Animal models; Animals; Apoptosis; Atrophy; Basal ganglia; Biochemistry; Biology; Brain; Brain - metabolism; Brain - pathology; Brain research; Caspase; Caspase-8; Cell death; Cell Death - drug effects; Central nervous system diseases; Cytotoxicity; Degeneration; Fas Ligand Protein - metabolism; Fas Ligand Protein - toxicity; fas Receptor - metabolism; FasL protein; Gene Expression; Genetic engineering; Human health and pathology; Humans; Inclusion bodies; Investigations; Life Sciences; Medicine; Mice; Middle Aged; Movement disorders; Multiple System Atrophy - genetics; Multiple System Atrophy - metabolism; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Nervous system diseases; Neurodegeneration; Neurodegenerative diseases; Neurosciences; Oligodendrocytes; Oligodendroglia - drug effects; Oligodendroglia - metabolism; Protein Binding; Protein Transport; Rats; Rodents; Signal Transduction; Synuclein; Toxicity; Transgenic mice; Denmark; Australia; Aarhus Denmark; Germany
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0055243

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.