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

Linkage of alpha -synuclein (alpha -SN) mutations to familiar Parkinson's d isease (PD) and presence of alpha -SN as a major constituent of Lewy body i n both sporadic and familial PD implicate alpha -SN abnormality in PD patho genesis. Here we demonstrate that overexpression of wildtype or mutant alph a -SN does not cause any deleterious effect on the growth or continued prop agation of transfected human cells, but overproduction of mutant alpha -SN heightens their sensitivity to menadione-induced oxidative injury. Such enh anced vulnerability is more pronounced in neuronal transfectants than in th eir nonneuronal counterparts and is associated with increased production of reactive oxygen species. The data suggest that mutated alpha -SN, especial ly with an alanine-to-proline substitution at residue 30, sensitizes neuron al cells to oxidative damage.