Over-expression of α-synuclein 98 triggers intracellular oxidative stress and enhances susceptibility to rotenone.

The α-synuclein protein is a major component of Lewy bodies found in the brains of patients with Parkinson's disease (PD). Recently, α-synuclein 98 (α-syn98), a small isoform of the wild type protein was isolated. The neurotoxicity of this protein was assessed by over-expressing α-syn98 in dopaminergic cells. Enhanced expression of α-syn98 was insufficient to adversely affect the survival of neurons or to promote aggregation of the protein. However, when exposed to rotenone, α-syn98 over-expressing dopaminergic cells demonstrated significantly increased cytotoxicity and aggregate formation. Furthermore, we found enhanced basal ROS production and MDA levels in α-syn98 over-expressing neurons. High basal oxidative stress induced by α-syn98, combined with oxidative stress caused by rotenone treatment, promoted aggregate formation and significantly decreased cell viability. These data indicate that α-syn98 can enhance the susceptibility of dopaminergic neurons to oxidative insults by raising steady-state levels of oxidative stress.