Sensitization of neuronal cells to oxidative stress with mutated human α-synuclein

Linkage of α-synuclein (α-SN) mutations to familial Parkinson's disease (PD) and presence of α-SN as a major constituent of Lewy body in both sporadic and familial PD implicate α-SN abnormality in PD pathogenesis. Here we demonstrate that overexpression of wild-type or mutant α-SN does not cause any deleterious effect on the growth or continued propagation of transfected human cells, but overproduction of mutant α-SN heightens their sensitivity to menadione-induced oxidative injury. Such enhanced vulnerability is more pronounced in neuronal transfectants than in their nonneuronal counterparts and is associated with increased production of reactive oxygen species. The data suggest that mutated α-SN, especially with an alanine-to-proline substitution at residue 30, sensitizes neuronal cells to oxidative damage.