α-Synuclein facilitates the toxicity of oxidized catechol metabolites: Implications for selective neurodegeneration in Parkinson’s disease

AbstractFree radicals, including dopamine (DA)-oxidized metabolites, have long been implicated in pathogenesis of Parkinson’s disease (PD). However, the relationships between such oxidative stresses and α-synuclein (α-S), a major constituent of Lewy bodies, remain unknown. In this study, we established neuronal cells that constitutively express α-S and tetracycline-regulated tyrosinase. While tyrosinase overexpression induced apoptosis, co-expression of wild type or A53T mutant human α-S with tyrosinase further exacerbated cell death. In this process, the formation of α-S oligomers and the reduction in mitochondrial membrane potential were demonstrated. This cellular model may reconstitute the pathological metabolism of α-S in the synucleinopathy and provide a useful tool to explore possible pathomechanisms of nigral degeneration in PD