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Transnitrosylation from DJ-1 to PTEN attenuates neuronal cell death in parkinson's disease models.

TitleTransnitrosylation from DJ-1 to PTEN attenuates neuronal cell death in parkinson's disease models.
Publication TypeJournal Article
Year of Publication2014
AuthorsChoi MSik, Nakamura T, Cho S-J, Han X, Holland EA, Qu J, Petsko GA, Yates JR, Liddington RC, Lipton SA
JournalJ Neurosci
Volume34
Issue45
Pagination15123-31
Date Published2014 Nov 05
ISSN1529-2401
KeywordsAged, Aged, 80 and over, Amino Acid Motifs, Amino Acid Sequence, Apoptosis, Case-Control Studies, Female, HEK293 Cells, Humans, Intracellular Signaling Peptides and Proteins, Male, Molecular Sequence Data, Mutation, Neurons, Nitric Oxide, Oncogene Proteins, Parkinson Disease, Protein Deglycase DJ-1, PTEN Phosphohydrolase
Abstract

Emerging evidence suggests that oxidative/nitrosative stress, as occurs during aging, contributes to the pathogenesis of Parkinson's disease (PD). In contrast, detoxification of reactive oxygen species and reactive nitrogen species can protect neurons. DJ-1 has been identified as one of several recessively inherited genes whose mutation can cause familial PD, and inactivation of DJ-1 renders neurons more susceptible to oxidative stress and cell death. DJ-1 is also known to regulate the activity of the phosphatase and tensin homolog (PTEN), which plays a critical role in neuronal cell death in response to various insults. However, mechanistic details delineating how DJ-1 regulates PTEN activity remain unknown. Here, we report that PTEN phosphatase activity is inhibited via a transnitrosylation reaction [i.e., transfer of a nitric oxide (NO) group from the cysteine residue of one protein to another]. Specifically, we show that DJ-1 is S-nitrosylated (forming SNO-DJ-1); subsequently, the NO group is transferred from DJ-1 to PTEN by transnitrosylation. Moreover, we detect SNO-PTEN in human brains with sporadic PD. Using x-ray crystallography and site-directed mutagenesis, we find that Cys106 is the site of S-nitrosylation on DJ-1 and that mutation of this site inhibits transnitrosylation to PTEN. Importantly, S-nitrosylation of PTEN decreases its phosphatase activity, thus promoting cell survival. These findings provide mechanistic insight into the neuroprotective role of SNO-DJ-1 by elucidating how DJ-1 detoxifies NO via transnitrosylation to PTEN. Dysfunctional DJ-1, which lacks this transnitrosylation activity due to mutation or prior oxidation (e.g., sulfonation) of the critical cysteine thiol, could thus contribute to neurodegenerative disorders like PD.

DOI10.1523/JNEUROSCI.4751-13.2014
Alternate JournalJ. Neurosci.
PubMed ID25378175
PubMed Central IDPMC4220036
Grant ListP41 GM103533 / GM / NIGMS NIH HHS / United States
R01 MH067880 / MH / NIMH NIH HHS / United States
P30 NS076411 / NS / NINDS NIH HHS / United States
HHSN268201000035C / HL / NHLBI NIH HHS / United States
R01 NS086890 / NS / NINDS NIH HHS / United States
P01 HD029587 / HD / NICHD NIH HHS / United States
P01 ES016738 / ES / NIEHS NIH HHS / United States
HHSN268201000035C / / PHS HHS / United States
P01 HD29587 / HD / NICHD NIH HHS / United States