Differential regulation of NMDA receptor function by DJ-1 and PINK1
Ning Chang
Division of Fundamental Neurobiology, Toronto Western Research Institute, University Health Network, Toronto, Ontario M5T 2S8, Canada
These authors contributed equally to this work.
Search for more papers by this authorLijun Li
Division of Fundamental Neurobiology, Toronto Western Research Institute, University Health Network, Toronto, Ontario M5T 2S8, Canada
These authors contributed equally to this work.
Search for more papers by this authorRong Hu
Department of Physiology and Cell Biology, University of Nevada School of Medicine, 1664 North Virginia Street, MS0352, Reno, NV 89557, USA
Department of Neurosurgery, Southwest Hospital, Chongqing 400038, China
Search for more papers by this authorYuexin Shan
Division of Fundamental Neurobiology, Toronto Western Research Institute, University Health Network, Toronto, Ontario M5T 2S8, Canada
Search for more papers by this authorBaosong Liu
Division of Fundamental Neurobiology, Toronto Western Research Institute, University Health Network, Toronto, Ontario M5T 2S8, Canada
Search for more papers by this authorLei Li
Research Institute of Surgery and Daping Hospital, Chongqing 400042, China
Search for more papers by this authorHanbin Wang
Department of Internal Medicine, 307 Hospital, Beijing, 100071, China
Search for more papers by this authorHua Feng
Department of Neurosurgery, Southwest Hospital, Chongqing 400038, China
Search for more papers by this authorDianshi Wang
Division of Fundamental Neurobiology, Toronto Western Research Institute, University Health Network, Toronto, Ontario M5T 2S8, Canada
Search for more papers by this authorCarol Cheung
Department of Pathology, University Health Network, Toronto, Ontario M5G 2C4, Canada
Search for more papers by this authorMingxia Liao
Department of Physiology and Cell Biology, University of Nevada School of Medicine, 1664 North Virginia Street, MS0352, Reno, NV 89557, USA
Search for more papers by this authorQi Wan
Division of Fundamental Neurobiology, Toronto Western Research Institute, University Health Network, Toronto, Ontario M5T 2S8, Canada
Department of Physiology and Cell Biology, University of Nevada School of Medicine, 1664 North Virginia Street, MS0352, Reno, NV 89557, USA
Search for more papers by this authorNing Chang
Division of Fundamental Neurobiology, Toronto Western Research Institute, University Health Network, Toronto, Ontario M5T 2S8, Canada
These authors contributed equally to this work.
Search for more papers by this authorLijun Li
Division of Fundamental Neurobiology, Toronto Western Research Institute, University Health Network, Toronto, Ontario M5T 2S8, Canada
These authors contributed equally to this work.
Search for more papers by this authorRong Hu
Department of Physiology and Cell Biology, University of Nevada School of Medicine, 1664 North Virginia Street, MS0352, Reno, NV 89557, USA
Department of Neurosurgery, Southwest Hospital, Chongqing 400038, China
Search for more papers by this authorYuexin Shan
Division of Fundamental Neurobiology, Toronto Western Research Institute, University Health Network, Toronto, Ontario M5T 2S8, Canada
Search for more papers by this authorBaosong Liu
Division of Fundamental Neurobiology, Toronto Western Research Institute, University Health Network, Toronto, Ontario M5T 2S8, Canada
Search for more papers by this authorLei Li
Research Institute of Surgery and Daping Hospital, Chongqing 400042, China
Search for more papers by this authorHanbin Wang
Department of Internal Medicine, 307 Hospital, Beijing, 100071, China
Search for more papers by this authorHua Feng
Department of Neurosurgery, Southwest Hospital, Chongqing 400038, China
Search for more papers by this authorDianshi Wang
Division of Fundamental Neurobiology, Toronto Western Research Institute, University Health Network, Toronto, Ontario M5T 2S8, Canada
Search for more papers by this authorCarol Cheung
Department of Pathology, University Health Network, Toronto, Ontario M5G 2C4, Canada
Search for more papers by this authorMingxia Liao
Department of Physiology and Cell Biology, University of Nevada School of Medicine, 1664 North Virginia Street, MS0352, Reno, NV 89557, USA
Search for more papers by this authorQi Wan
Division of Fundamental Neurobiology, Toronto Western Research Institute, University Health Network, Toronto, Ontario M5T 2S8, Canada
Department of Physiology and Cell Biology, University of Nevada School of Medicine, 1664 North Virginia Street, MS0352, Reno, NV 89557, USA
Search for more papers by this authorSummary
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.
References
- Aleyasin H, Rousseaux MW, Phillips M, Kim RH, Bland RJ, Callaghan S, Slack RS, During MJ, Mak TW, Park DS (2007) The Parkinson’s disease gene DJ-1 is also a key regulator of stroke-induced damage. Proc. Natl. Acad. Sci. USA 104, 18748–18753.
- Anastasio NC, Xia Y, O’Connor ZR, Johnson KM (2009) Differential role of N-methyl-d-aspartate receptor subunits 2A and 2B in mediating phencyclidine-induced perinatal neuronal apoptosis and behavioral deficits. Neuroscience 163, 1181–1191.
- Andres-Mateos E, Perier C, Zhang L, Blanchard-Fillion B, Greco TM, Thomas B, Ko HS, Sasaki M, Ischiropoulos H, Przedborski S, Dawson TM, Dawson VL (2007) DJ-1 gene deletion reveals that DJ-1 is an atypical peroxiredoxin-like peroxidase. Proc. Natl. Acad. Sci. USA 104, 14807–14812.
- Beilina A, Van Der Brug M, Ahmad R, Kesavapany S, Miller DW, Petsko GA, Cookson MR (2005) Mutations in PTEN-induced putative kinase 1 associated with recessive parkinsonism have differential effects on protein stability. Proc. Natl. Acad. Sci. USA 102, 5703–5708. Epub 2005 Apr 5711.
- Blackinton JG, Anvret A, Beilina A, Olson L, Cookson MR, Galter D (2007) Expression of PINK1 mRNA in human and rodent brain and in Parkinson’s disease. Brain Res. 1184, 10–16.
- Bonifati V, Rizzu P, Squitieri F, Krieger E, Vanacore N, Van Swieten JC, Brice A, Van Duijn CM, Oostra B, Meco G, Heutink P (2003) DJ-1(PARK7), a novel gene for autosomal recessive, early onset parkinsonism. Neurol. Sci. 24, 159–160.
- Brewer GJ, Torricelli JR, Evege EK, Price PJ (1993) Optimized survival of hippocampal neurons in B27-supplemented Neurobasal, a new serum-free medium combination. J. Neurosci. Res. 35, 567–576.
- Canet-Aviles RM, Wilson MA, Miller DW, Ahmad R, McLendon C, Bandyopadhyay S, Baptista MJ, Ringe D, Petsko GA, Cookson MR (2004) The Parkinson’s disease protein DJ-1 is neuroprotective due to cysteine-sulfinic acid-driven mitochondrial localization. Proc. Natl. Acad. Sci. USA 101, 9103–9108.
- Carroll RC, Zukin RS (2002) NMDA-receptor trafficking and targeting: implications for synaptic transmission and plasticity. Trends Neurosci. 25, 571–577.
- Chang N, El-Hayek YH, Gomez E, Wan Q (2007) Phosphatase PTEN in neuronal injury and brain disorders. Trends Neurosci. 30, 581–586.
- Choi WS, Eom DS, Han BS, Kim WK, Han BH, Choi EJ, Oh TH, Markelonis GJ, Cho JW, Oh YJ (2004) Phosphorylation of p38 MAPK induced by oxidative stress is linked to activation of both caspase-8- and -9-mediated apoptotic pathways in dopaminergic neurons. J. Biol. Chem. 279, 20451–20460.
- Deas E, Plun-Favreau H, Wood NW (2009) PINK1 function in health and disease. EMBO Mol. Med. 1, 152–165.
- DeRidder MN, Simon MJ, Siman R, Auberson YP, Raghupathi R, Meaney DF (2006) Traumatic mechanical injury to the hippocampus in vitro causes regional caspase-3 and calpain activation that is influenced by NMDA receptor subunit composition. Neurobiol. Dis. 22, 165–176.
- Dingledine R, Borges K, Bowie D, Traynelis SF (1999) The glutamate receptor ion channels. Pharmacol. Rev. 51, 7–61.
- Von Engelhardt J, Coserea I, Pawlak V, Fuchs EC, Kohr G, Seeburg PH, Monyer H (2007) Excitotoxicity in vitro by NR2A- and NR2B-containing NMDA receptors. Neuropharmacology 53, 10–17.
- Fantin M, Auberson YP, Morari M (2008) Differential effect of NR2A and NR2B subunit selective NMDA receptor antagonists on striato-pallidal neurons: relationship to motor response in the 6-hydroxydopamine model of parkinsonism. J. Neurochem. 106, 957–968.
- Gautier CA, Kitada T, Shen J (2008) Loss of PINK1 causes mitochondrial functional defects and increased sensitivity to oxidative stress. Proc. Natl. Acad. Sci. USA 105, 11364–11369.
- Greenwood SM, Connolly CN (2007) Dendritic and mitochondrial changes during glutamate excitotoxicity. Neuropharmacology 53, 891–898.
- Haque ME, Thomas KJ, D’Souza C, Callaghan S, Kitada T, Slack RS, Fraser P, Cookson MR, Tandon A, Park DS (2008) Cytoplasmic Pink1 activity protects neurons from dopaminergic neurotoxin MPTP. Proc. Natl. Acad. Sci. USA 105, 1716–1721.
- Hardingham GE, Fukunaga Y, Bading H (2002) Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways. Nat. Neurosci. 5, 405–414.
- Healy DG, Abou-Sleiman PM, Gibson JM, Ross OA, Jain S, Gandhi S, Gosal D, Muqit MM, Wood NW, Lynch T (2004) PINK1 (PARK6) associated Parkinson disease in Ireland. Neurology 63, 1486–1488.
- Hoyte L, Barber PA, Buchan AM, Hill MD (2004) The rise and fall of NMDA antagonists for ischemic stroke. Curr. Mol. Med. 4, 131–136.
- Kim DH, Behlke MA, Rose SD, Chang MS, Choi S, Rossi JJ (2005a) Synthetic dsRNA Dicer substrates enhance RNAi potency and efficacy. Nat. Biotechnol. 23, 222–226.
- Kim RH, Peters M, Jang Y, Shi W, Pintilie M, Fletcher GC, DeLuca C, Liepa J, Zhou L, Snow B, Binari RC, Manoukian AS, Bray MR, Liu FF, Tsao MS, Mak TW (2005b) DJ-1, a novel regulator of the tumor suppressor PTEN. Cancer Cell 7, 263–273.
- Kim RH, Smith PD, Aleyasin H, Hayley S, Mount MP, Pownall S, Wakeham A, You-Ten AJ, Kalia SK, Horne P, Westaway D, Lozano AM, Anisman H, Park DS, Mak TW (2005c) Hypersensitivity of DJ-1-deficient mice to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine (MPTP) and oxidative stress. Proc. Natl. Acad. Sci. USA 102, 5215–5220.
- Kitada T, Pisani A, Porter DR, Yamaguchi H, Tscherter A, Martella G, Bonsi P, Zhang C, Pothos EN, Shen J (2007) Impaired dopamine release and synaptic plasticity in the striatum of PINK1-deficient mice. Proc. Natl. Acad. Sci. USA 104, 11441–11446.
- Koutsilieri E, Riederer P (2007) Excitotoxicity and new antiglutamatergic strategies in Parkinson’s disease and Alzheimer’s disease. Parkinsonism Relat. Disord. 13(Suppl. 3), S329–S331.
- Lee JM, Zipfel GJ, Choi DW (1999) The changing landscape of ischaemic brain injury mechanisms. Nature 399, A7–A14.
- Lipton SA (2004) Failures and successes of NMDA receptor antagonists: molecular basis for the use of open-channel blockers like memantine in the treatment of acute and chronic neurologic insults. NeuroRx. 1, 101–110.
- Liu F, Wan Q, Pristupa ZB, Yu XM, Wang YT, Niznik HB (2000) Direct protein-protein coupling enables cross-talk between dopamine D5 and gamma-aminobutyric acid A receptors. Nature 403, 274–280.
- Liu B, Liao M, Mielke JG, Ning K, Chen Y, Li L, El-Hayek YH, Gomez E, Zukin RS, Fehlings MG, Wan Q (2006) Ischemic insults direct glutamate receptor subunit 2-lacking AMPA receptors to synaptic sites. J. Neurosci. 26, 5309–5319.
- Liu Y, Wong TP, Aarts M, Rooyakkers A, Liu L, Lai TW, Wu DC, Lu J, Tymianski M, Craig AM, Wang YT (2007) NMDA receptor subunits have differential roles in mediating excitotoxic neuronal death both in vitro and in vivo. J. Neurosci. 27, 2846–2857.
- Liu B, Li L, Zhang Q, Chang N, Wang D, Shan Y, Wang H, Feng H, Zhang L, Brann DW, Wan Q (2010) Preservation of GABAA receptor function by PTEN inhibition protects against neuronal death in ischemic stroke. Stroke 41, 1018–1026.
- Martel MA, Wyllie DJ, Hardingham GE (2009). In developing hippocampal neurons, NR2B-containing N-methyl-d-aspartate receptors (NMDARs) can mediate signaling to neuronal survival and synaptic potentiation, as well as neuronal death. Neuroscience 158, 334–343.
- Mo JS, Kim MY, Ann EJ, Hong JA, Park HS (2008) DJ-1 modulates UV-induced oxidative stress signaling through the suppression of MEKK1 and cell death. Cell Death Differ. 15, 1030–1041.
- Nagakubo D, Taira T, Kitaura H, Ikeda M, Tamai K, Iguchi-Ariga SM, Ariga H (1997) DJ-1, a novel oncogene which transforms mouse NIH3T3 cells in cooperation with ras. Biochem. Biophys. Res. Commun. 231, 509–513.
- Ning K, Pei L, Liao M, Liu B, Zhang Y, Jiang W, Mielke JG, Li L, Chen Y, El-Hayek YH, Fehlings MG, Zhang X, Liu F, Eubanks J, Wan Q (2004) Dual neuroprotective signaling mediated by downregulating two distinct phosphatase activities of PTEN. J. Neurosci. 24, 4052–4060.
- Plun-Favreau H, Hardy J (2008) PINK1 in mitochondrial function. Proc. Natl. Acad. Sci. USA 105, 11041–11042.
- Rumbaugh G, Vicini S (1999) Distinct synaptic and extrasynaptic NMDA receptors in developing cerebellar granule neurons. J. Neurosci. 19, 10603–10610.
- Schmid AC, Byrne RD, Vilar R, Woscholski R (2004) Bisperoxovanadium compounds are potent PTEN inhibitors. FEBS Lett. 566, 35–38.
- Schotanus SM, Chergui K (2008) NR2A-containing NMDA receptors depress glutamatergic synaptic transmission and evoked-dopamine release in the mouse striatum. J. Neurochem. 106, 1758–1765.
- Shan Y, Liu B, Li L, Chang N, Li L, Wang H, Wang D, Feng H, Cheung C, Liao M, Cui T, Sugita S, Wan Q (2009) Regulation of PINK1 by NR2B-containing NMDA receptors in ischemic neuronal injury. J. Neurochem. 111, 1149–1160.
- Silvestri L, Caputo V, Bellacchio E, Atorino L, Dallapiccola B, Valente EM, Casari G (2005) Mitochondrial import and enzymatic activity of PINK1 mutants associated to recessive parkinsonism. Hum. Mol. Genet. 14, 3477–3492.
- Tang B, Xiong H, Sun P, Zhang Y, Wang D, Hu Z, Zhu Z, Ma H, Pan Q, Xia JH, Xia K, Zhang Z (2006) Association of PINK1 and DJ-1 confers digenic inheritance of early-onset Parkinson’s disease. Hum. Mol. Genet. 15, 1816–1825.
- Thomas KJ, Cookson MR (2009) The role of PTEN-induced kinase 1 in mitochondrial dysfunction and dynamics. Int. J. Biochem. Cell Biol. 41, 2025–2035.
- Tovar KR, Westbrook GL (1999) The incorporation of NMDA receptors with a distinct subunit composition at nascent hippocampal synapses in vitro. J. Neurosci. 19, 4180–4188.
- Unoki M, Nakamura Y (2001) Growth-suppressive effects of BPOZ and EGR2, two genes involved in the PTEN signaling pathway. Oncogene 20, 4457–4465.
- Valente EM, Abou-Sleiman PM, Caputo V, Muqit MM, Harvey K, Gispert S, Ali Z, Del Turco D, Bentivoglio AR, Healy DG, Albanese A, Nussbaum R, Gonzalez-Maldonado R, Deller T, Salvi S, Cortelli P, Gilks WP, Latchman DS, Harvey RJ, Dallapiccola B, Auburger G, Wood NW (2004) Hereditary early-onset Parkinson’s disease caused by mutations in PINK1. Science 304, 1158–1160. Epub 2004 Apr 1115.
- Vasseur S, Afzal S, Tardivel-Lacombe J, Park DS, Iovanna JL, Mak TW (2009) DJ-1/PARK7 is an important mediator of hypoxia-induced cellular responses. Proc. Natl. Acad. Sci. USA 106, 1111–1116.
- Wan Q, Xiong ZG, Man HY, Ackerley CA, Braunton J, Lu WY, Becker LE, MacDonald JF, Wang YT (1997) Recruitment of functional GABA(A) receptors to postsynaptic domains by insulin. Nature 388, 686–690.
- Wang D, Qian L, Xiong H, Liu J, Neckameyer WS, Oldham S, Xia K, Wang J, Bodmer R, Zhang Z (2006) Antioxidants protect PINK1-dependent dopaminergic neurons in Drosophila. Proc. Natl. Acad. Sci. USA 103, 13520–13525.
- Wang C, Sadovova N, Ali HK, Duhart HM, Fu X, Zou X, Patterson TA, Binienda ZK, Virmani A, Paule MG, Slikker W Jr, Ali SF (2007) l-carnitine protects neurons from 1-methyl-4-phenylpyridinium-induced neuronal apoptosis in rat forebrain culture. Neuroscience 144, 46–55.
- Wood-Kaczmar A, Gandhi S, Yao Z, Abramov AS, Miljan EA, Keen G, Stanyer L, Hargreaves I, Klupsch K, Deas E, Downward J, Mansfield L, Jat P, Taylor J, Heales S, Duchen MR, Latchman D, Tabrizi SJ, Wood NW (2008) PINK1 is necessary for long term survival and mitochondrial function in human dopaminergic neurons. PLoS ONE 3, e2455.
- Yanagisawa D, Kitamura Y, Inden M, Takata K, Taniguchi T, Morikawa S, Morita M, Inubushi T, Tooyama I, Taira T, Iguchi-Ariga SM, Akaike A, Ariga H (2008) DJ-1 protects against neurodegeneration caused by focal cerebral ischemia and reperfusion in rats. J. Cereb. Blood Flow Metab. 28, 563–578.
- Yang Y, Gehrke S, Haque ME, Imai Y, Kosek J, Yang L, Beal MF, Nishimura I, Wakamatsu K, Ito S, Takahashi R, Lu B (2005) Inactivation of Drosophila DJ-1 leads to impairments of oxidative stress response and phosphatidylinositol 3-kinase/Akt signaling. Proc. Natl. Acad. Sci. USA 102, 13670–13675.
- Zhang L, Shimoji M, Thomas B, Moore DJ, Yu SW, Marupudi NI, Torp R, Torgner IA, Ottersen OP, Dawson TM, Dawson VL (2005) Mitochondrial localization of the Parkinson’s disease related protein DJ-1: implications for pathogenesis. Hum. Mol. Genet. 14, 2063–2073.
