RGD Reference Report - Differential regulation of NMDA receptor function by DJ-1 and PINK1. - Rat Genome Database

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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.
RGD ID: 13463453
Pubmed: PMID:20698836   (View Abstract at PubMed)
DOI: DOI:10.1111/j.1474-9726.2010.00615.x   (Journal Full-text)

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.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

Objects Annotated

Genes (Rattus norvegicus)
Park7  (Parkinsonism associated deglycase)
Pink1  (PTEN induced kinase 1)


Additional Information