【摘 要】
：
Dysfunction of PINK1 or DJ-1 promotes neuronal death and is implicated in the pathogenesis of neurodegenerative diseases, but the underlying mechanisms remain unclear.Given the roles of N-methyl-D-asp
【机 构】
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Department of Physiology & Cell Biology University of Nevada School of Medicine USA
【出 处】
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BIT`s 3rd Annual World Congress of NeuroTalk-2012(2012第三届国际神
论文部分内容阅读
Dysfunction of PINK1 or DJ-1 promotes neuronal death and is implicated in the pathogenesis of neurodegenerative diseases, 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 over-activation 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 survivalpromoting 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.
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