-Synuclein Phosphorylation and Nitration in Parkinson’s Disease

Parkinson’s disease (PD) is the second most common neurodegenerative disease, affecting six million people worldwide. PD results from the specific loss of substantia nigra dopaminergic neurons. Aggregation of one protein, -synuclein, is characteristic of PD. This aggregation is thought to be a critical step in the etiology of the disease. While the molecular mechanism of -synuclein aggregation remains unknown, nitrative stress and phosphorylation have been implicated in synuclein modification and aggregation. In fact, nitration of -synuclein tyrosine residues 39, 125, 133 or 136, may be an early event in aggregates, Lewy bodies, seen in PD. Furthermore, nitrative stress leads to the induction of -synuclein aggregation at a higher rate than seen in other PD mutants. This aggregation may result from a stabilization of pre-assembled -synuclein filaments, which, upon nitration, may withstand denaturing conditions and enhance formation of SDS-insoluble, heat-stable high mass aggregates. Phosphorylation of a-synuclein also appears to play a critical role in the formation of aggregates. Extensive studies indicate that -synuclein found in PD patient brains is extensively phosphorylated. Phosphorylation of ser-129 may enhance formation of aggregates reminiscent of Lewy bodies in vitro and in vivo. Nitration and phosphorylation of synuclein may be key to the mechanisms underlying the formation of Lewy bodies in PD.