Effect of the overexpression of wild-type or mutant α-synuclein on cell susceptibility to insult

Mutations in α-synuclein (A30P and A53T) are involved in some cases of familial Parkinson's disease (FPD), but it is not known how they result in nigral cell death. We examined the effect of α-synuclein overexpression on the response of cells to various insults. Wild-type α-synuclein and α-synuclein mutations associated with FPD were overexpressed in NT-2/D1 and SK-N-MC cells. Overexpression of wild-type α-synuclein delayed cell death induced by serum withdrawal or H₂O₂, but did not delay cell death induced by 1-methyl-4-phenylpyridinium ion (MPP⁺). By contrast, wild-type α-synuclein transfectants were sensitive to viability loss induced by staurosporine, lactacystin or 4-hydroxy-2-transnonenal (HNE). Decreases in glutathione (GSH) levels were attenuated by wild-type α-synuclein after serum deprivation, but were aggravated following lactacystin or staurosporine treatment. Mutant α-synucleins increased levels of 8-hydroxyguanine, protein carbonyls, lipid peroxidation and 3-nitrotyrosine, and markedly accelerated cell death in response to all the insults examined. The decrease in GSH levels was enhanced in mutant α-synuclein transfectants. The loss of viability induced by toxic insults was by apoptosic mechanism. The presence of abnormal α-synucleins in substantia nigra in PD may increase neuronal vulnerability to a range of toxic agents.