title: Differential regulation of NMDA receptor function by DJ-1 and PINK1.
abstract: 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.
authors.affiliation: Toronto Western Research Institute, University Health Network, Toronto, Ontario, Canada.
authors.forename: Ning
authors.initials: N
authors.lastname: Chang
authors.forename: Lijun
authors.initials: L
authors.lastname: Li
authors.forename: Rong
authors.initials: R
authors.lastname: Hu
authors.forename: Yuexin
authors.initials: Y
authors.lastname: Shan
authors.forename: Baosong
authors.initials: B
authors.lastname: Liu
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.forename: Hanbin
authors.initials: H
authors.lastname: Wang
authors.forename: Hua
authors.initials: H
authors.lastname: Feng
authors.forename: Dianshi
authors.initials: D
authors.lastname: Wang
authors.forename: Carol
authors.initials: C
authors.lastname: Cheung
authors.forename: Mingxia
authors.initials: M
authors.lastname: Liao
authors.forename: Qi
authors.initials: Q
authors.lastname: Wan
mesh_terms: D000818:Animals; D016923:Cell Death; D002470:Cell Survival; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D009474:Neurons / Q000166:cytology; D009924:Organ Culture Techniques; D000071617:Protein Deglycase DJ-1; D011494:Protein Kinases / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D015398:Signal Transduction; D000099202:PTEN-Induced Putative Kinase
chemical_list: D008869:Microtubule-Associated Proteins; D000071617:Protein Deglycase DJ-1; D011494:Protein Kinases; D016194:Receptors, N-Methyl-D-Aspartate; D000099202:PTEN-Induced Putative Kinase; C404267:PARK7 protein, rat