Nitrosative Stress Linked to Sporadic Parkinson's Disease: S-nitrosylation of Parkin Regulates Its E3 Ubiquitin Ligase Activity

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2004 Jul 15

PMID 15252205

Citations 238

Authors

Dongdong Yao

Zezong Gu

Tomohiro Nakamura

Zhong-Qing Shi

Yuliang Ma

Benjamin Gaston

Lisa A Palmer

Edward M Rockenstein

Zhuohua Zhang

Eliezer Masliah

Takashi Uehara

Stuart A Lipton

Affiliations

Soon will be listed here.

Abstract

Many hereditary and sporadic neurodegenerative disorders are characterized by the accumulation of aberrant proteins. In sporadic Parkinson's disease, representing the most prevalent movement disorder, oxidative and nitrosative stress are believed to contribute to disease pathogenesis, but the exact molecular basis for protein aggregation remains unclear. In the case of autosomal recessive-juvenile Parkinsonism, mutation in the E3 ubiquitin ligase protein parkin is linked to death of dopaminergic neurons. Here we show both in vitro and in vivo that nitrosative stress leads to S-nitrosylation of wild-type parkin and, initially, to a dramatic increase followed by a decrease in the E3 ligase-ubiquitin-proteasome degradative pathway. The initial increase in parkin's E3 ubiquitin ligase activity leads to autoubiquitination of parkin and subsequent inhibition of its activity, which would impair ubiquitination and clearance of parkin substrates. These findings may thus provide a molecular link between free radical toxicity and protein accumulation in sporadic Parkinson's disease.

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