Differential regulation of NMDA receptor function by DJ-1 and PINK1.

Authors: Chang, Ning  Li, Lijun  Hu, Rong  Shan, Yuexin  Liu, Baosong  Li, Lei  Wang, Hanbin  Feng, Hua  Wang, Dianshi  Cheung, Carol  Liao, Mingxia  Wan, Qi 
Citation: Chang N, etal., Aging Cell. 2010 Oct;9(5):837-50. doi: 10.1111/j.1474-9726.2010.00615.x.
Pubmed: (View Article at PubMed) PMID:20698836
DOI: Full-text: DOI:10.1111/j.1474-9726.2010.00615.x

Dysfunction of PTEN-induced kinase 1 (PINK1) or DJ-1 promotes neuronal death and is implicated in the pathogenesis of Parkinson's disease, but the underlying mechanisms remain unclear. Given the roles of N-methyl-d-aspartate receptor (NMDAr)-mediated neurotoxicity in various brain disorders including cerebral ischemia and neurodegenerative diseases, we investigated the effects of PINK1 and DJ-1 on NMDAr function. Using protein overexpression and knockdown approaches, we showed that PINK1 increased NMDAr-mediated whole-cell currents by enhancing the function of NR2A-containing NMDAr subtype (NR2ACNR). However, DJ-1 decreased NMDAr-mediated currents, which was mediated through the inhibition of both NR2ACNR and NR2B-containing NMDAr subtype (NR2BCNR). We revealed that the knockdown of DJ-1 enhanced PTEN expression, which not only potentiated NR2BCNR function but also increased PINK1 expression that led to NR2ACNR potentiation. These results indicate that NMDAr function is differentially regulated by DJ-1-dependent signal pathways DJ-1/PTEN/NR2BCNR and DJ-1/PTEN/PINK1/NR2ACNR. Our results further showed that the suppression of DJ-1, while promoted NMDA-induced neuronal death through the overactivation of PTEN/NR2BCNR-dependent cell death pathway, induced a neuroprotective effect to counteract DJ-1 dysfunction-mediated neuronal death signaling through activating PTEN/PINK1/NR2ACNR cell survival-promoting pathway. Thus, PINK1 acts with DJ-1 in a common pathway to regulate NMDAr-mediated neuronal death. This study suggests that the DJ-1/PTEN/NR2BCNR and DJ-1/PTEN/PINK1/NR2ACNR pathways may represent potential therapeutic targets for the development of neuroprotection strategy in the treatment of brain injuries and neurodegenerative diseases such as Parkinson's disease.

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CRRD ID: 13463453
Created: 2017-12-13
Species: All species
Last Modified: 2017-12-13
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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.