Differential regulation of NMDA receptor function by DJ-1 and PINK1.
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.
Chang
Ning
N
Toronto Western Research Institute, University Health Network, Toronto, Ontario, Canada.
Li
Lijun
L
Hu
Rong
R
Shan
Yuexin
Y
Liu
Baosong
B
Li
Lei
L
Wang
Hanbin
H
Feng
Hua
H
Wang
Dianshi
D
Cheung
Carol
C
Liao
Mingxia
M
Wan
Qi
Q
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
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