S-Nitrosylation of parkin as a novel regulator of p53-mediated neuronal cell death in sporadic Parkinson’s disease

Molecular Neurodegeneration

Stuart A Lipton¹  Nobuki Nakanishi²  Eliezer Masliah¹  Traci Fang Newmeyer²  Shing Fai Chan²  Anthony Adame¹  Michael Mante¹  Edward Rockenstein¹  Tomohiro Nakamura²  Carmen R Sunico² 

[1] Department of Neurosciences and Pathology, University of California at San Diego, 9500, Gilman Drive, La Jolla, CA 92039, USA;Sanford-Burnham Medical Research Institute, Del E. Webb Center for Neuroscience, Aging, and Stem Cell Research, 10901, North Torrey Pines Road, La Jolla, CA 92037, USA

关键词: Parkinson’s disease;    Nitrosative stress;    p53;    Parkin;    S-nitrosylation;    Nitric oxide (NO);   

Others  :  862203
DOI  :  10.1186/1750-1326-8-29

 received in 2013-06-01, accepted in 2013-08-16,  发布年份 2013

【 摘 要 】

Background

Mutations in the gene encoding parkin, a neuroprotective protein with dual functions as an E3 ubiquitin ligase and transcriptional repressor of p53, are linked to familial forms of Parkinson’s disease (PD). We hypothesized that oxidative posttranslational modification of parkin by environmental toxins may contribute to sporadic PD.

Results

We first demonstrated that S-nitrosylation of parkin decreased its activity as a repressor of p53 gene expression, leading to upregulation of p53. Chromatin immunoprecipitation as well as gel-shift assays showed that parkin bound to the p53 promoter, and this binding was inhibited by S-nitrosylation of parkin. Additionally, nitrosative stress induced apoptosis in cells expressing parkin, and this death was, at least in part, dependent upon p53. In primary mesencephalic cultures, pesticide-induced apoptosis was prevented by inhibition of nitric oxide synthase (NOS). In a mouse model of pesticide-induced PD, both S-nitrosylated (SNO-)parkin and p53 protein levels were increased, while administration of a NOS inhibitor mitigated neuronal death in these mice. Moreover, the levels of SNO-parkin and p53 were simultaneously elevated in postmortem human PD brain compared to controls.

Conclusions

Taken together, our data indicate that S-nitrosylation of parkin, leading to p53-mediated neuronal cell death, contributes to the pathophysiology of sporadic PD.

【 授权许可】

   
2013 Sunico et al.; licensee BioMed Central Ltd.

【 图 表 】

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