Oxidative post‐translational modifications of α‐synuclein in the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) mouse model of Parkinson's disease

Abstract

Structural and functional alterations of α‐synuclein is a presumed culprit in the demise of dopaminergic neurons in Parkinson's disease (PD). α‐Synuclein mutations are found in familial but not in sporadic PD, raising the hypothesis that effects similar to those of familial PD‐linked α‐synuclein mutations may be achieved by oxidative post‐translational modifications. Here, we show that wild‐type α‐synuclein is a selective target for nitration following peroxynitrite exposure of stably transfected HEK293 cells. Nitration of α‐synuclein also occurs in the mouse striatum and ventral midbrain following administration of the parkinsonian neurotoxin 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP). Conversely, β‐synuclein and synaptophysin were not nitrated in MPTP‐intoxicated mice. Our data demonstrate that α‐synuclein is a target for tyrosine nitration, which, by disrupting its biophysical properties, may be relevant to the putative role of α‐synuclein in the neurodegeneration associated with MPTP toxicity and with PD.