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.
Department of Biomedicine, Aarhus University, Aarhus, Denmark.
Christine L
CL
Kragh
Gwenaëlle
G
Fillon
Amanda
A
Gysbers
Hanne D
HD
Hansen
Manuela
M
Neumann
Christiane
C
Richter-Landsberg
Christian
C
Haass
Bernard
B
Zalc
Catherine
C
Lubetzki
Wei-Ping
WP
Gai
Glenda M
GM
Halliday
Philipp J
PJ
Kahle
Poul H
PH
Jensen
D000368:Aged; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D053222:Fas Ligand Protein / Q000378:metabolism / Q000633:toxicity; D015870:Gene Expression; D006801:Humans; D051379:Mice; D008875:Middle Aged; D019578:Multiple System Atrophy / Q000235:genetics* / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009836:Oligodendroglia / Q000187:drug effects / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport; D051381:Rats; D015398:Signal Transduction; D051844:alpha-Synuclein / Q000235:genetics* / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism*
D053222:Fas Ligand Protein; D009419:Nerve Tissue Proteins; C547161:TPPP protein, mouse; D051844:alpha-Synuclein; D019014:fas Receptor