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• W2007844529 abstract "The dysfunction of proteasomes and mitochondria has been implicated in the pathogenesis of Parkinson disease. However, the mechanism by which this dysfunction causes neuronal cell death is unknown. We studied the role of cyclin-dependent kinase 5 (Cdk5)-p35 in the neuronal cell death induced by 1-methyl-4-phenylpyrinidinium ion (MPP+), which has been used as an in vitro model of Parkinson disease. When cultured neurons were treated with 100 μm MPP+, p35 was degraded by proteasomes at 3 h, much earlier than the neurons underwent cell death at 12–24 h. The degradation of p35 was accompanied by the down-regulation of Cdk5 activity. We looked for the primary target of MPP+ that triggered the proteasome-mediated degradation of p35. MPP+ treatment for 3 h induced the fragmentation of the mitochondria, reduced complex I activity of the respiratory chain without affecting ATP levels, and impaired the mitochondrial import system. The dysfunction of the mitochondrial import system is suggested to up-regulate proteasome activity, leading to the ubiquitin-independent degradation of p35. The overexpression of p35 attenuated MPP+-induced neuronal cell death. In contrast, depletion of p35 with short hairpin RNA not only induced cell death but also sensitized to MPP+ treatment. These results indicate that a brief MPP+ treatment triggers the delayed neuronal cell death by the down-regulation of Cdk5 activity via mitochondrial dysfunction-induced up-regulation of proteasome activity. We propose a role for Cdk5-p35 as a survival factor in countering MPP+-induced neuronal cell death. The dysfunction of proteasomes and mitochondria has been implicated in the pathogenesis of Parkinson disease. However, the mechanism by which this dysfunction causes neuronal cell death is unknown. We studied the role of cyclin-dependent kinase 5 (Cdk5)-p35 in the neuronal cell death induced by 1-methyl-4-phenylpyrinidinium ion (MPP+), which has been used as an in vitro model of Parkinson disease. When cultured neurons were treated with 100 μm MPP+, p35 was degraded by proteasomes at 3 h, much earlier than the neurons underwent cell death at 12–24 h. The degradation of p35 was accompanied by the down-regulation of Cdk5 activity. We looked for the primary target of MPP+ that triggered the proteasome-mediated degradation of p35. MPP+ treatment for 3 h induced the fragmentation of the mitochondria, reduced complex I activity of the respiratory chain without affecting ATP levels, and impaired the mitochondrial import system. The dysfunction of the mitochondrial import system is suggested to up-regulate proteasome activity, leading to the ubiquitin-independent degradation of p35. The overexpression of p35 attenuated MPP+-induced neuronal cell death. In contrast, depletion of p35 with short hairpin RNA not only induced cell death but also sensitized to MPP+ treatment. These results indicate that a brief MPP+ treatment triggers the delayed neuronal cell death by the down-regulation of Cdk5 activity via mitochondrial dysfunction-induced up-regulation of proteasome activity. We propose a role for Cdk5-p35 as a survival factor in countering MPP+-induced neuronal cell death. Parkinson disease (PD) 3The abbreviations used are: PDParkinson diseaseAP52-amino-5-phosphonovaleric acidCdkcyclin-dependent kinaseDAPI4′,6-diamidino-2-phenylindoleDIVdays in vitroDTTdithiothreitolE3ubiquitin-protein isopeptide ligaseEGFPenhanced green fluorescent proteinGFPgreen fluorescent proteinl-NAMEN-nitro-l-arginine methyl ester hydrochlorideMPP1-methyl-4-phenylpyrinidiniumNACN-acetyl-l-cysteinePBNphenyl N-t-butylnitronePBSphosphate-buffered salineTRIM1-(2-trifluromethyl phenyl)imidazoleshRNAshort hairpin RNAERKextracellular signal-regulated protein kinaseNMDAN-methyl-d-aspartateTricineN-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]glycine. 3The abbreviations used are: PDParkinson diseaseAP52-amino-5-phosphonovaleric acidCdkcyclin-dependent kinaseDAPI4′,6-diamidino-2-phenylindoleDIVdays in vitroDTTdithiothreitolE3ubiquitin-protein isopeptide ligaseEGFPenhanced green fluorescent proteinGFPgreen fluorescent proteinl-NAMEN-nitro-l-arginine methyl ester hydrochlorideMPP1-methyl-4-phenylpyrinidiniumNACN-acetyl-l-cysteinePBNphenyl N-t-butylnitronePBSphosphate-buffered salineTRIM1-(2-trifluromethyl phenyl)imidazoleshRNAshort hairpin RNAERKextracellular signal-regulated protein kinaseNMDAN-methyl-d-aspartateTricineN-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]glycine. is the second most common neurodegenerative disease, characterized pathologically by degenerated dopaminergic neurons and ubiquitin-positive aggregates known as Lewy bodies (1Thomas B. Beal M.F. Hum. Mol. Genet. 2007; 16: 183-194Crossref PubMed Scopus (669) Google Scholar). Most cases of PD are sporadic, but a small proportion of patients with PD have the familial form. Several causative genes have been identified for familial PDs, including α-synuclein (2Polymeropoulos M.H. Lavedon D. Leroy E. Ide S.E. Dehejia A. Dutra A. Pike B. Root H. Rubenstein J. Boyer R. Stenroos E.S. Chandrasekharappa S. Athanassiadou A. Papapetropoulos T. Johnson W.G. Lazzarini A.M. Duvoisin R.C. Di Iorio G. Golbe L.I. Nussbaum R.L. Science. 1997; 276: 2045-2047Crossref PubMed Scopus (6515) Google Scholar), ubiquitin C-terminal hydrolase L1 (UCH-L1) (3Leroy E. Boyer R. Auburger G. Leube B. Ulm G. Mezey E. Harta G. Brownstein M.J. Jonnalagada S. Chernova T. Dehejia A. Lavedan C. Gasser T. Steinbach P.J. Wilkinson K.D. Polymeropoulos M.H. Nature. 1998; 395: 451-452Crossref PubMed Scopus (1372) Google Scholar), and parkin, an ubiquitin ligase E3 of the ubiquitin-proteasome system (4Kitada T. Asakawa S. Hattori N. Matsumine H. Yamamura Y. Minoshima S. Yokochi M. Mizuno Y. Shimizu N. Nature. 1998; 392: 605-608Crossref PubMed Scopus (4124) Google Scholar), implicating the impairment of the ubiquitin-proteasome pathway in the pathogenesis of PD. However, the mechanisms underlying the involvement of the ubiquitin-proteasome system in the development of PD are not yet understood.The 1-methyl-4-phenylpyrinidinium ion (MPP+), a toxic metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), is a neurotoxin used widely to induce dopaminergic neuronal cell death in in vitro models of PD (5Mytilineou C. Cohen G. Heikkila R.E. Neurosci. Lett. 1985; 57: 19-24Crossref PubMed Scopus (74) Google Scholar). Previous studies have indicated that MPP+ induces neuronal cell death via several pathways, including the inhibition of complex I activity of the respiratory chain in mitochondria, leading to energy depletion, protein peroxidation, and DNA damage by producing reactive oxygen species and the induction of cytotoxic glutamate secretion (6Dauer W. Przedborski S. Neuron. 2003; 39: 889-909Abstract Full Text Full Text PDF PubMed Scopus (3977) Google Scholar, 7Jackson-Lewis V. Smeyne R.J. Neurotox. Res. 2005; 7: 193-202Crossref PubMed Scopus (70) Google Scholar). However, the precise molecular pathway resulting in neuronal cell death remains to be identified.Cyclin-dependent kinase 5 (Cdk5) is a member of the Cdk serine/threonine kinase family. Cdk5 plays a role in a variety of neuronal activities including neuronal migration during central nervous system development (8Ohshima T. Ward J.M. Huh C.G. Longenecker G. Veeranna Pant H.C. Brady R.O. Martin L.J. Kulkarni A.B. Proc. Natl. Acad. Sci. U.S.A. 1996; 93: 11173-11178Crossref PubMed Scopus (802) Google Scholar, 9Chae T. Kwon Y.T. Bronson R. Dikkes P. Li E. Tsai L.H. Neuron. 1997; 18: 29-42Abstract Full Text Full Text PDF PubMed Scopus (656) Google Scholar), synaptic activity in matured neurons (10Cheung Z.H. Ip N.Y. Biotechnol. J. 2007; 2: 949-957Crossref PubMed Scopus (64) Google Scholar), and neuronal cell death in neurodegenerative diseases (11Nguyen M.D. Lavirière R.C. Julien J.P. Neuron. 2001; 30: 135-147Abstract Full Text Full Text PDF PubMed Scopus (299) Google Scholar, 12Bu B. Li J. Davies P. Vincent I. J. Neurosci. 2002; 22: 6515-6525Crossref PubMed Google Scholar). Generally, when Cdk5 are activated by their respective activator cyclins, they function in cell cycle progression. However, unlike those cell cycle Cdk5, the kinase activity of Cdk5 is detected mainly in post mitotic neurons. This is because Cdk5 activators p35 and p39 are expressed predominantly in neurons (13Hisanaga S. Saito T. NeuroSignals. 2003; 12: 221-229Crossref PubMed Scopus (78) Google Scholar, 14Cruz J.C. Tsai L.H. Trends Mol. Med. 2004; 9: 452-458Abstract Full Text Full Text PDF Scopus (213) Google Scholar). The amount of p35 is the major determinant of Cdk5 activity, and it is normally a short-lived protein degraded by the ubiquitin-proteasome pathway (15Patrick G.N. Zhou P. Kwon Y.T. Howley P.M. Tsai L.H. J. Biol. Chem. 1998; 273: 24057-24064Abstract Full Text Full Text PDF PubMed Scopus (261) Google Scholar, 16Saito T. Ishiguro K. Onuki R. Nagai Y. Kishimoto T. Hisanaga S. Biochem. Biophys. Res. Commun. 1998; 252: 775-778Crossref PubMed Scopus (38) Google Scholar). However, in stressed neurons, the calcium-activated protease calpain cleaves p35 to the more stable and active form, p25 (17Patrick G.N. Zukerberg L. Nikolic M. de la Monte S. Dikkes P. Tsai L.H. Nature. 1999; 402: 615-622Crossref PubMed Scopus (1307) Google Scholar, 18Kusakawa G. Saito T. Onuki R. Ishiguro K. Kishimoto T. Hisanaga S. J. Biol. Chem. 2000; 275: 17166-17172Abstract Full Text Full Text PDF PubMed Scopus (334) Google Scholar, 19Lee M.S. Kwon Y.T. Li M. Peng J. Friedlander R.M. Tsai L.H. Nature. 2000; 405: 360-364Crossref PubMed Scopus (901) Google Scholar, 20O'Hare M.J. Kushwaha N. Zhang Y. Aleyasin H. Callaghan S.M. Slack R.S. Albert P.R. Vincent I. Park D.S. J. Neurosci. 2005; 25: 8954-8966Crossref PubMed Scopus (116) Google Scholar, 21Saito T. Konno T. Hosokawa T. Asada A. Ishiguro K. Hisanaga S. J. Neurochem. 2007; 102: 133-140Crossref PubMed Scopus (51) Google Scholar). Hyperactivated or mislocalized Cdk5-p25 has been implicated in the pathogenesis of numerous neurodegenerative disorders including PD and Alzheimer disease. In the case of PD, Cdk5 and p35 are found in the Lewy bodies of the dopaminergic neurons of the brain (22Brion J.P. Couck A.M. Am. J. Pathol. 1995; 147: 1465-1476PubMed Google Scholar, 23Nakamura S. Kawamoto Y. Nakano S. Akiguchi I. Kimura J. Acta Neuropathol. 1997; 94: 153-157Crossref PubMed Scopus (77) Google Scholar). Cdk5 is activated by p25 and is required for cell death in mouse models of PD induced with MPTP (24Smith P.D. Crocker S.J. Jackson-Lewis V. Jordan-Sciutto K.L. Hayley S. Mount M.P. O'Hare M.J. Callaghan S. Slack R.S. Przedborski S. Anisman H. Park D.S. Proc. Natl. Acad. Sci. U.S.A. 2003; 100: 13650-13655Crossref PubMed Scopus (263) Google Scholar) or 6-hydroxydopamine (25Neystat M. Rzhetskaya M. Oo T.F. Kholodilov N. Yarygina O. Wilson A. El-Khodor B.F. Burke R.E. J. Neurochem. 2001; 77: 1611-1625Crossref PubMed Scopus (35) Google Scholar). It has been shown that Cdk5-p25 in MPTP-treated neurons phosphorylates the survival factor, myocyte enhancer factor 2 (MEF2), to inactivate it, leading to cell death (26Smith P.D. Mount M.P. Shree R. Callaghan S. Slack R.S. Anisman H. Vincent I. Wang X. Mao Z. Park D.S. J. Neurosci. 2006; 26: 440-447Crossref PubMed Scopus (162) Google Scholar, 27Gong X. Tang X. Wiedmann M. Wang X. Peng J. Zheng D. Blair L.A. Marshall J. Mao Z. Neuron. 2003; 38: 33-46Abstract Full Text Full Text PDF PubMed Scopus (241) Google Scholar). However, further studies are required to clarify the involvement of p35 metabolism in the PD pathway.Contrary to its role in cell death progression, recent studies have also suggested a survival function for Cdk5 in maintaining survival signals or counteracting apoptotic signals. For example, Cdk5 inhibits c-Jun phosphorylation by c-Jun-N-terminal protein kinase 3, which is activated by UV irradiation (28Li B.S. Zhang L. Takahashi S. Ma W. Jaffe H. Kulkarni A.B. Pant H.C. EMBO J. 2002; 21: 324-333Crossref PubMed Scopus (122) Google Scholar). Cdk5 also promotes the survival of neurons by activating Akt through the well known neuregulin/phosphatidylinositol 3-kinase (PI3K) survival pathway, which leads to the down-regulation of proapoptotic factors (29Li B.S. Ma W. Jaffe H. Zheng Y. Takahashi S. Zhang L. Kulkarni A.B. Pant H.C. J. Biol. Chem. 2003; 278: 35702-35709Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar). Cdk5 attenuates cell death either by up-regulating Bcl-2 through the phosphorylation of ERK (30Wang C.X. Song J.H. Song D.K. Yong V.W. Shuaib A. Hao C. Cell Death Differ. 2006; 13: 1203-1212Crossref PubMed Scopus (85) Google Scholar) or by phosphorylating Bcl-2 to maintain its neuroprotective effect (31Cheung Z.H. Gong K. Ip N.Y. J. Neurosci. 2008; 28: 4872-4877Crossref PubMed Scopus (65) Google Scholar). However, whether Cdk5 acts as the anti-apoptotic factor in the PD model of neuronal cell death has not been determined.Here, we studied the role of Cdk5-p35 in the cell death of neurons treated with MPP+. We found that p35 was proteolysed in cultured neurons by either calpain or proteasomes depending on the concentration of MPP+ used. The proteasomal MPP+-induced degradation of p35 occurred earlier and at lower MPP+ concentrations than did its cleavage by calpain. MPP+ up-regulated the overall proteasome activity in the neurons by impairing the mitochondrial protein import system. A brief MPP+ treatment for up to ∼3 h was sufficient to induce delayed cell death at 24 h. The overexpression of p35 suppressed this MPP+-induced cell death, and depletion of p35 increased cell death. Together, these results implicate a role for Cdk5-p35 as a survival factor in MPP+-treated neurons.DISCUSSIONHere, we studied the effects of MPP+ on the metabolism of p35, which is a major determinant of Cdk5 activity, using mouse brain cortical neurons. High concentrations of MPP+ (500–1000 μm) induced the cleavage of p35 to p25 when neuronal cell death occurred. Conversely, MPP+ at concentrations even lower than 100 μm induced the proteasomal degradation of p35 before the neurons underwent cell death. We found that this brief treatment with MPP+ caused the impairment of mitochondrial protein import, resulting in increased proteasomal activity, which led to the degradation of p35 and then the inactivation of Cdk5 activity. The short term MPP+ treatment was also sufficient to commit neuronal cell death. The expression of p35 suppressed the cell death progression of MPP+-treated neurons. In contrast, knockdown of p35 increased the cell death. These results indicate that Cdk5-p35 functions as a survival factor during MPP+-induced neuronal commitment to cell death.Two different types of p35 proteolysis were observed in primary neurons treated with MPP+ in both a time- and concentration-dependent manner. The cleavage of p35 to p25 was shown to result in the higher Cdk5 activity accompanied by its mislocalization, leading to cell death. This type of MPP+ action has already been reported in cultured neurons and MPTP-treated mice as a model of PD (24Smith P.D. Crocker S.J. Jackson-Lewis V. Jordan-Sciutto K.L. Hayley S. Mount M.P. O'Hare M.J. Callaghan S. Slack R.S. Przedborski S. Anisman H. Park D.S. Proc. Natl. Acad. Sci. U.S.A. 2003; 100: 13650-13655Crossref PubMed Scopus (263) Google Scholar, 26Smith P.D. Mount M.P. Shree R. Callaghan S. Slack R.S. Anisman H. Vincent I. Wang X. Mao Z. Park D.S. J. Neurosci. 2006; 26: 440-447Crossref PubMed Scopus (162) Google Scholar). Cdk5-p25 thus generated translocates into the nucleus to inactivate the survival factor MEF2 by phosphorylation. However, the degradation of p35 induced by a brief MPP+ treatment is attributable to a distinct effect of MPP+ on p35 metabolism. In this case, p35 was rapidly degraded without the generation of p25 by the proteasome, and Cdk5 activity was down-regulated as a result of this p35 degradation. This down-regulation might have been missed in previous studies because the major focus was on the generation of p25 and the consequent cell death.A number of studies have measured the proteasomal activity in MPP+-treated neurons, but their results are controversial, with some reports describing inactivation or no effect and others activation. MPP+ itself does not affect the proteolytic activity of isolated 20S proteasome (39Alves da Costa C. Dunys J. Brau F. Wilk S. Cappai R. Checler F. J. Biol. Chem. 2006; 281: 9824-9831Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar). Therefore, MPP+ should affect, if any, proteasome activity indirectly through intracellular environmental changes or regulatory factors, most likely mitochondrial dysfunction as discussed below. The down-regulation of proteasome activity is detected mainly after longer MPP+ treatments, e.g. for ∼24 h both in cultured cells (40Höglinger G.U. Carrard G. Michel P.P. Medja F. Lombès A. Ruberg M. Friguet B. Hirsch E.C. J. Neurochem. 2003; 86: 1297-1307Crossref PubMed Scopus (229) Google Scholar) and mouse brain (41Fornai F. Schlüter O.M. Lenzi P. Gesi M Ruffoli R Ferrucci M. Lazzeri G. Busceti C.L. Pontarelli F. Battaglia G. Pellegrini A. Nicoletti F. Ruggieri S. Paparelli A. Südhof T.C. Proc. Natl. Acad. Sci. U.S.A. 2005; 102: 3413-3418Crossref PubMed Scopus (416) Google Scholar). In these cases, long term treatment with MPP+ disrupts mitochondrial complex I activity, resulting in the depletion of ATP. Because the proteasome requires ATP for the degradation of its target proteins, the depletion of ATP may lead to the down-regulation of proteasome activity. This impaired ubiquitin-proteasome pathway is thought to be relevant to the neuronal degeneration of PD. It has been reported that MPP+ does not alter the proteasome activity in TSM-1 and SH-SY5Y neuronal cell lines (39Alves da Costa C. Dunys J. Brau F. Wilk S. Cappai R. Checler F. J. Biol. Chem. 2006; 281: 9824-9831Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar). In this report, proteasome activity was examined by the degradation of α-synuclein 8 h after MPP+ or 6-hydroxydopamine (6-OHDA) treatment. MPP+ did not affect the proteasomal degradation of α-synuclein, whereas 6-OHDA inactivated 20S proteasome both in vitro and in vivo through oxidative stress. In contrast, several studies have reported increased proteasome activity as observed here. MPP+ induces the rapid proteasomal degradation of short-lived proteins such as Ret protein in PC12 cells (42Hirata Y. Kiuchi K. J. Neurochem. 2007; 102: 1606-1613Crossref PubMed Scopus (6) Google Scholar) and cyclin D1 in MG63 osteosarcoma cells and HeLa cells (43Bai J. Nakamura H. Ueda S. Kwon Y.W. Tanaka T. Ban S. Yodoi J. J. Biol. Chem. 2004; 279: 38710-38714Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar). Proteasome activity, when measured with a peptide substrates, is elevated by exposure to 10 or 100 μm MPP+ for 2 h (44Sawada H. Kohno R. Kihara T. Izumi Y. Sakka N. Ibi M. Nakanishi M. Nakamizo T. Yamakawa K. Shibasaki H. Yamamoto N. Akaike A. Inden M. Kitamura Y. Taniguchi T. Shimohama S. J. Biol. Chem. 2004; 279: 10710-10719Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar). Taking these results together, the above discrepancies could be derived from differences in experimental conditions such as treatment time, types of cells or proteins analyzed. Although systematic studies will be required, MPP+ may affect proteasome activity biphasically, with activation followed by inactivation. MPP+ apparently had no effect after 8 h of treatment (39Alves da Costa C. Dunys J. Brau F. Wilk S. Cappai R. Checler F. J. Biol. Chem. 2006; 281: 9824-9831Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar) when activation turned to inactivation.Because rotenone, a more specific complex I inhibitor, showed an effect similar to MPP+ on the degradation of p35, we assumed that mitochondrial dysfunction occurs upstream of p35 degradation. Complex I inhibition would disrupt the mitochondrial membrane potential, which is required for mitochondrial protein import (45Hood D.A. Joseph A.M. Proc. Nutr. Soc. 2004; 63: 293-300Crossref PubMed Scopus (31) Google Scholar). In fact, it has been shown that MPP+ reduces the mitochondrial membrane potential, which ultimately causes cell death (46Chalmers-Redman R.M. Fraser A.D. Carlile G.W. Pong A. Tatton W.G. Biochem. Biophys. Res. Commun. 1999; 257: 440-447Crossref PubMed Scopus (53) Google Scholar, 47Shang T. Joseph J. Hillard C.J. Kalyanaraman B. J. Biol. Chem. 2005; 280: 34644-34653Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar). Although we could not demonstrate this conclusively, several indirect lines of evidence suggest that the mitochondrial import system is an intermediate between complex I inhibition and proteasome activation. MPP+ inhibited the import of GFP-mito and Su9-EGFP into the mitochondria. Mitochondrial proteins would similarly fail to be imported into the mitochondria. If mitochondrial proteins are not imported into the mitochondria properly, they are degraded rapidly by proteasomes (48Granot Z. Kobiler O. Melamed-Book N. Eimerl S. Bahat A. Lu B. Braun S. Maurizi M.R. Suzuki C.K. Oppenheim A.B. Orly J. Mol. Endocrinol. 2007; 21: 2164-2177Crossref PubMed Scopus (99) Google Scholar). For example, preornithine transcarbamylase is degraded by proteasomes in the cytosol when its import is inhibited by oxidative stress (38Wright G. Terada K. Yano M. Sergeev I. Mori M. Exp. Cell Res. 2001; 263: 107-117Crossref PubMed Scopus (90) Google Scholar). A slight increase in mitochondrial proteins in the cytoplasm may enhance the degradation activity of the proteasome. This may be a kind of quality control system imposed by mitochondrial dysfunction. Although p35 is not a mitochondrial protein, the increased proteasomal activity may also target short-lived proteins such as p35.The degradation of p35 in cortical neurons is stimulated by glutamate (35Wei F.Y. Tomizawa K. Ohshima T. Asada A. Saito T. Nguyen C. Bibb J.A. Ishiguro K. Kulkarni A.B. Pant H.C. Mikoshiba K. Matsui H. Hisanaga S. et al.J. Neurochem. 2005; 93: 502-512Crossref PubMed Scopus (78) Google Scholar). However, the MPP+-induced degradation of p35 appears to be distinct from that induced by glutamate. Whereas the glutamate-dependent degradation of p35 is transient and physiological, its MPP+-induced degradation appears long lasting and pathological, as demonstrated by the fact that p35 did not recover even after the MPP+ was washed out. Whereas the autophosphorylation of p35 by Cdk5 is required for its glutamate-induced degradation, this was not observed for its MPP+-induced degradation. Ubiquitination of p35 was also decreased in MPP+-treated neurons. Some short-lived proteins are degraded by the ubiquitin-independent proteasome pathway (49Kahana C. Asher G. Shaul Y. Cell Cycle. 2005; 4: 1461-1464Crossref PubMed Scopus (45) Google Scholar). It is well known that ornithine decarboxylase is degraded independently of ubiquitin by the 20S (50Asher G. Bercovich Z. Tsvetkov P. Shaul Y. Kahana C. Mol. Cell. 2005; 17: 645-655Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar) and 26S (51Murakami Y. Matsufuji S. Kameji T. Hayashi S. Igarashi K. Tamura T. Tanaka K. Ichihara A. Nature. 1992; 360: 597-599Crossref PubMed Scopus (666) Google Scholar) proteasomes. p53 and cyclin D1 are also degraded by the ubiquitin-independent proteasome pathway, in addition to the ubiquitin-dependent one (52Asher G. Lotem J. Sachs L. Kahana C. Shaul Y. Proc. Natl. Acad. Sci. U.S.A. 2002; 99: 13125-13130Crossref PubMed Scopus (191) Google Scholar, 53Newman R.M. Mobascher A. Mangold U. Koike C. Diah S. Schmidt M. Finley D. Zetter B.R. J. Biol. Chem. 2004; 279: 41504-41511Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar). Ubiquitin-independent proteasomal degradation has been demonstrated for several mitochondrial proteins. For example, steroidogenic acute regulatory protein (StAR) is proteolysed independently of ubiquitin in the cytoplasm by proteasomes (48Granot Z. Kobiler O. Melamed-Book N. Eimerl S. Bahat A. Lu B. Braun S. Maurizi M.R. Suzuki C.K. Oppenheim A.B. Orly J. Mol. Endocrinol. 2007; 21: 2164-2177Crossref PubMed Scopus (99) Google Scholar). Preornithine transcarbamylase is degraded in the cytoplasm by proteasomes when mitochondrial import is inhibited by Paraquat (38Wright G. Terada K. Yano M. Sergeev I. Mori M. Exp. Cell Res. 2001; 263: 107-117Crossref PubMed Scopus (90) Google Scholar), but its ubiquitination was not detected despite extensive experimental efforts. These results implicate MPP+ as an inducer of the ubiquitin-independent degradation of p35 downstream of mitochondrial import impairment.The brief treatment with MPP+ down-regulated Cdk5 activity by degrading p35, leading to the commitment to cell death. We found that the neuronal cell death was counteracted by the overexpression of p35. These results suggested the role of Cdk5-p35 as a survival factor. This was supported by the experiment showing that depletion of p35 in neurons with shRNA increased cell death, consistent with the results that knockdown of Cdk5 induces neuronal cell death (31Cheung Z.H. Gong K. Ip N.Y. J. Neurosci. 2008; 28: 4872-4877Crossref PubMed Scopus (65) Google Scholar). Treatment with MPP+ may trigger cell death commitment by down-regulating Cdk5 activity through the degradation of p35. Several recent reports show a role for Cdk5-p35 as a survival factor in neurons. For example, Cdk5 activates the phosphatidylinositol 3/Akt pathway by phosphorylating ErB2 and ErB3 to down-regulate proapoptotic signals (29Li B.S. Ma W. Jaffe H. Zheng Y. Takahashi S. Zhang L. Kulkarni A.B. Pant H.C. J. Biol. Chem. 2003; 278: 35702-35709Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar). Cdk5 also stimulates ERK to up-regulate the anti-apoptotic factor Bcl-2 (30Wang C.X. Song J.H. Song D.K. Yong V.W. Shuaib A. Hao C. Cell Death Differ. 2006; 13: 1203-1212Crossref PubMed Scopus (85) Google Scholar) or to directly phosphorylate Bcl-2 at Ser-70 to maintain neuronal survival activity. Restored Cdk5 expression in Cdk5 null mice rescues their phenotype and perinatal mortality (54Tanaka T. Veeranna Ohshima T. Rajan P. Amin N.D. Cho A. Sreenath T. Pant H.C. Brady R.O. Kulkarni A.B. J. Neurosci. 2001; 21: 550-558Crossref PubMed Google Scholar). A question for future research is how Cdk5 activity counters MPP+-mediated cell death signals.MPP+ is a drug that is used frequently to induce the cell death of dopaminergic neurons in models of PD. Previous studies have argued that MPP+ causes neuronal cell death through several different pathways, including the generation of reactive oxygen species, the secretion of cytotoxic glutamate, and mitochondrial dysfunction (6Dauer W. Przedborski S. Neuron. 2003; 39: 889-909Abstract Full Text Full Text PDF PubMed Scopus (3977) Google Scholar). It is important to understand which pathway is critical to the induction of cell death. Our results raise another possibility, that the down-regulation of Cdk5 activity triggers the commitment to cell death much earlier than previously thought. The ectopic overactivation of proteasome systems followed by Cdk5 down-regulation may also be involved in the commitment to cell death in neurodegenerative disorders such as PD. Parkinson disease (PD) 3The abbreviations used are: PDParkinson diseaseAP52-amino-5-phosphonovaleric acidCdkcyclin-dependent kinaseDAPI4′,6-diamidino-2-phenylindoleDIVdays in vitroDTTdithiothreitolE3ubiquitin-protein isopeptide ligaseEGFPenhanced green fluorescent proteinGFPgreen fluorescent proteinl-NAMEN-nitro-l-arginine methyl ester hydrochlorideMPP1-methyl-4-phenylpyrinidiniumNACN-acetyl-l-cysteinePBNphenyl N-t-butylnitronePBSphosphate-buffered salineTRIM1-(2-trifluromethyl phenyl)imidazoleshRNAshort hairpin RNAERKextracellular signal-regulated protein kinaseNMDAN-methyl-d-aspartateTricineN-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]glycine. 3The abbreviations used are: PDParkinson diseaseAP52-amino-5-phosphonovaleric acidCdkcyclin-dependent kinaseDAPI4′,6-diamidino-2-phenylindoleDIVdays in vitroDTTdithiothreitolE3ubiquitin-protein isopeptide ligaseEGFPenhanced green fluorescent proteinGFPgreen fluorescent proteinl-NAMEN-nitro-l-arginine methyl ester hydrochlorideMPP1-methyl-4-phenylpyrinidiniumNACN-acetyl-l-cysteinePBNphenyl N-t-butylnitronePBSphosphate-buffered salineTRIM1-(2-trifluromethyl phenyl)imidazoleshRNAshort hairpin RNAERKextracellular signal-regulated protein kinaseNMDAN-methyl-d-aspartateTricineN-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]glycine. is the second most common neurodegenerative disease, characterized pathologically by degenerated dopaminergic neurons and ubiquitin-positive aggregates known as Lewy bodies (1Thomas B. Beal M.F. Hum. Mol. Genet. 2007; 16: 183-194Crossref PubMed Scopus (669) Google Scholar). Most cases of PD are sporadic, but a small proportion of patients with PD have the familial form. Several causative genes have been identified for familial PDs, including α-synuclein (2Polymeropoulos M.H. Lavedon D. Leroy E. Ide S.E. Dehejia A. Dutra A. Pike B. Root H. Rubenstein J. Boyer R. Stenroos E.S. Chandrasekharappa S. Athanassiadou A. Papapetropoulos T. Johnson W.G. Lazzarini A.M. Duvoisin R.C. Di Iorio G. Golbe L.I. Nussbaum R.L. Science. 1997; 276: 2045-2047Crossref PubMed Scopus (6515) Google Scholar), ubiquitin C-terminal hydrolase L1 (UCH-L1) (3Leroy E. Boyer R. Auburger G. Leube B. Ulm G. Mezey E. Harta G. Brownstein M.J. Jonnalagada S. Chernova T. Dehejia A. Lavedan C. Gasser T. Steinbach P.J. Wilkinson K.D. Polymeropoulos M.H. Nature. 1998; 395: 451-452Crossref PubMed Scopus (1372) Google Scholar), and parkin, an ubiquitin ligase E3 of the ubiquitin-proteasome system (4Kitada T. Asakawa S. Hattori N. Matsumine H. Yamamura Y. Minoshima S. Yokochi M. Mizuno Y. Shimizu N. Nature. 1998; 392: 605-608Crossref PubMed Scopus (4124) Google Scholar), implicati" @default.
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• W2007844529 title "Commitment of 1-Methyl-4-phenylpyrinidinium Ion-induced Neuronal Cell Death by Proteasome-mediated Degradation of p35 Cyclin-dependent Kinase 5 Activator" @default.
• W2007844529 cites W1503570667 @default.
• W2007844529 cites W1520955829 @default.
• W2007844529 cites W1529020147 @default.
• W2007844529 cites W1563116834 @default.
• W2007844529 cites W1577397450 @default.
• W2007844529 cites W1618846043 @default.
• W2007844529 cites W1849680308 @default.
• W2007844529 cites W1877873625 @default.
• W2007844529 cites W1963485518 @default.
• W2007844529 cites W1964819733 @default.
• W2007844529 cites W1964830067 @default.
• W2007844529 cites W1972151119 @default.
• W2007844529 cites W1979014608 @default.
• W2007844529 cites W1979212852 @default.
• W2007844529 cites W1979490186 @default.
• W2007844529 cites W1979507013 @default.
• W2007844529 cites W1981713105 @default.
• W2007844529 cites W1983601892 @default.
• W2007844529 cites W1986817930 @default.
• W2007844529 cites W1989971341 @default.
• W2007844529 cites W1994912327 @default.
• W2007844529 cites W1997243628 @default.
• W2007844529 cites W2006469044 @default.
• W2007844529 cites W2010560152 @default.
• W2007844529 cites W2018667542 @default.
• W2007844529 cites W2020008529 @default.
• W2007844529 cites W2021958350 @default.
• W2007844529 cites W2038901745 @default.
• W2007844529 cites W2039603759 @default.
• W2007844529 cites W2041497934 @default.
• W2007844529 cites W2051570559 @default.
• W2007844529 cites W2056709569 @default.
• W2007844529 cites W2061004773 @default.
• W2007844529 cites W2061015706 @default.
• W2007844529 cites W2068009600 @default.
• W2007844529 cites W2068336600 @default.
• W2007844529 cites W2072368664 @default.
• W2007844529 cites W2085197560 @default.
• W2007844529 cites W2093832364 @default.
• W2007844529 cites W2096991937 @default.
• W2007844529 cites W2098261833 @default.
• W2007844529 cites W2116850877 @default.
• W2007844529 cites W2117743221 @default.
• W2007844529 cites W2127443571 @default.
• W2007844529 cites W2128672762 @default.
• W2007844529 cites W2146880144 @default.
• W2007844529 cites W2150656456 @default.
• W2007844529 cites W2151498829 @default.
• W2007844529 cites W2157811690 @default.
• W2007844529 cites W2168380686 @default.
• W2007844529 cites W4246230178 @default.
• W2007844529 cites W62603772 @default.
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