Differential cytotoxicity of dopamine and H2O2 in a human neuroblastoma divided cell line transfected with α-synuclein and its familial Parkinson's disease-linked mutants

a-Synuclein accumulates in Lewy bodies and two missense mutations, A30P and A53T, have been linked to familial Parkinson's disease. Neither the normal function of a-synuclein nor the pathomechanism of alpha-synuclein-induced neuropathy are known. SK-N-MC neuroblastoma cells were transiently transfected with either wt alpha-synuclein, or its mutants, and their abilities to protect against oxidative stress were assessed. At low expression levels (1 mug cDNA/10(5) cells), all three synuclein variants were devoid of any effect on dopamine-induced cytotoxicity and nitrite production, whereas at higher expression (5 mug cDNA/l 05 cells), the variants enhanced dopamine-mediated effects. Low levels of wt a-synuclein blocked H2O2-induced cytotoxicity and nitrite production, a protective effect that was partly decreased upon higher expression. Both A30P and A53T increased in a dose-dependent manner H2O2-induced nitrite production and cell death. These results show an absence of protective effects for the A30P/A53T mutants, and a differential cytoprotective role of alpha-synuclein against oxidants, which varies according to expression levels. (C) 2003 Elsevier Science Ireland Ltd. All rights reserved.