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
Date Published2014 Nov 05
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

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.

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