Nitrosative stress linked to sporadic Parkinson's disease: S-nitrosylation of parkin regulates its E3 ubiquitin ligase activity

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

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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.

Original languageEnglish
Pages (from-to)10810-10814
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume101
Issue number29
DOIs
Publication statusPublished - Jul 20 2004
Externally publishedYes

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    Yao, D., Gu, Z., Nakamura, T., Shi, Z. Q., Ma, Y., Gaston, B., Palmer, L. A., Rockenstein, E. M., Zhang, Z., Masliah, E., Uehara, T., & Lipton, S. A. (2004). Nitrosative stress linked to sporadic Parkinson's disease: S-nitrosylation of parkin regulates its E3 ubiquitin ligase activity. Proceedings of the National Academy of Sciences of the United States of America, 101(29), 10810-10814. https://doi.org/10.1073/pnas.0404161101