Intracellular aggregation of alpha-synuclein is a neuropathological hallmark of a
variety of neurodegenerative diseases, including Parkinson's disease and multiple
system atrophy (MSA). The deposition of the normally neuronal alpha-synuclein protein
within (oligodendro)glial cytoplasmic inclusions (GCIs) and its relationship with
oligodendrocyte death in MSA have not been elucidated. We developed a cellular model
that recapitulates features of the degenerative process that occurs in MSA. Ectopic
human alpha-synuclein expression in primary oligodendrocytes was achieved by deriving
cultures from transgenic mice, which express human alpha-synuclein under the control
of the myelin proteolipid protein promoter. High level of alpha-synuclein expression
in oligodendrocytes induced alpha-synuclein accumulation, proteasome dysfunction and
alters their sensitivity to proteasome inhibition. The large perinuclear inclusions
formed, displayed biochemical and histological features of GCIs including the presence
of phosphorylated and oxidized forms of alpha-synuclein as well as components of the
ubiquitin-proteasome system and molecular chaperones. The fibrillar (amyloid) nature
of alpha-synuclein inclusions was indicated by thioflavin S staining and proven by
immunoelectron microscopy. Under these conditions, alpha-synuclein accumulation was
accompanied by oligodendrocyte apoptosis, as evidenced by caspase-3 activation and
chromatin condensation. These effects were not due to secondary effects of proteasome
inhibitors, because high-level over-expression by lentiviral delivery of alpha-synuclein
alone, but not beta-synuclein, caused protein aggregation and cell death. Moreover,
lenti-beta-synuclein prevented aggregation in alpha-synuclein transgenic oligodendrocytes
challenged with proteasome inhibitor. Thus, induction of alpha-synuclein and pathological
impairment of the ubiquitin-proteasome system may synergistically contribute to GCI
formation and ultimately cause oligodendrocyte dysfunction and cell death in MSA.
Support Contributed by: DFG, SFB 596, project A1.
