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.