title: S-Nitrosylation of parkin as a novel regulator of p53-mediated neuronal cell death in sporadic Parkinson's disease.
abstract: 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.
authors.affiliation: 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. slipton@sanfordburnham.org.
authors.forename: Carmen R
authors.initials: CR
authors.lastname: Sunico
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Nakamura
authors.forename: Edward
authors.initials: E
authors.lastname: Rockenstein
authors.forename: Michael
authors.initials: M
authors.lastname: Mante
authors.forename: Anthony
authors.initials: A
authors.lastname: Adame
authors.forename: Shing Fai
authors.initials: SF
authors.lastname: Chan
authors.forename: Traci Fang
authors.initials: TF
authors.lastname: Newmeyer
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
authors.forename: Nobuki
authors.initials: N
authors.lastname: Nakanishi
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Lipton
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D015153:Blotting, Western; D047369:Chromatin Immunoprecipitation; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010575:Pesticides / Q000633:toxicity; D011499:Protein Processing, Post-Translational; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D010575:Pesticides; D016159:Tumor Suppressor Protein p53; D009569:Nitric Oxide; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein