To explore pathogenesis of synucleinopathy including Parkinson's disease and multiple system atrophy, we developed cellular model for synucleinopathy. In this experimental model, α-synuclein was overexpressed in SH-SY5Y cells, which were then exposed to mitochondrial toxins. The data thus obtained suggested the followings.
1) By the treatment with rotenone, wild type α-synuclein overexpressing cells demonstrated intracellular aggregations, which shared a number of features with Lewy bodies.
2) The aggregate formation of α-synuclein may be cytoprotective.
3) The catechol-derived quinones are candidate molecules to facilitate the oligomer formation of α-synuclein.
4) The cells overexpressing S129A mutant showed few aggregations. It is suggested that phosphorylation at serine 129 is essential for aggregate formation.
5) In wild-type α-synuclein cells treated with rotenone, unfolded protein response (UPR) markers were induced prior to the induction of mitochondrial disruption and caspase-3 activation.
6) On the other hand, the S129A mutant failed to activate these UPRs. Thus it seems plausible that α-synuclein toxicity is dependent on the phosphorylation at S129.
