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. 2011 Jun 4;27(3):185–196. doi: 10.1007/s12264-011-1002-z

Cell cycle reactivation in mature neurons: a link with brain plasticity, neuronal injury and neurodegenerative diseases?

成熟神经元的细胞周期再活化与大脑可塑性、 神经元损伤和神经退行性疾病的关系

Karina Hernández-Ortega 1, Ricardo Quiroz-Baez 1,2, Clorinda Arias 1,
PMCID: PMC5560358  PMID: 21614101

Abstract

Although the cell cycle machinery is essentially linked to cellular proliferation, recent findings suggest that neuronal cell death is frequently concurrent with the aberrant expression of cell cycle proteins in post-mitotic neurons. The present work reviews the evidence of cell cycle reentry and expression of cell cycle-associated proteins as a complex response of neurons to insults in the adult brain but also as a mechanism underlying brain plasticity. The basic aspects of cell cycle mechanisms, as well as the evidence showing cell cycle protein expression in the injured brain, are reviewed. The discussion includes recent experimental work attempting to establish a correlation between altered brain plasticity and neuronal death, and an analysis of recent evidence on how neural cell cycle dysregulation is related to neurodegenerative diseases especially the Alzheimer’s disease. Understanding the mechanisms that control reexpression of proteins required for cell cycle progression which is involved in brain remodeling, may shed new light into the mechanisms involved in neuronal demise under diverse pathological circumstances. This would provide valuable clues about the possible therapeutic targets, leading to potential treatment of presently challenging neurodegenerative diseases.

Keywords: Alzheimer’s disease, cell cycle, neurodegeneration, brain plasticity

References

  • [1].Graña X., Reddy E.P. Cell cycle control in mammalian cells: role of cyclins, cyclins dependent kinases (CDKs), growth suppressor genes and cyclin-dependent kinase inhibitors (CDKIs) Oncogene. 1995;11:211–219. [PubMed] [Google Scholar]
  • [2].Lees E. Cyclin dependent kinase regulation. Curr Opin Cell Biol. 1995;7:773–780. doi: 10.1016/0955-0674(95)80060-3. [DOI] [PubMed] [Google Scholar]
  • [3].Frank C.L., Tsai L.H. Alternative functions of core cell cycle regulators in neuronal migration, neuronal maturation, and synaptic plasticity. Neuron. 2009;62:312–326. doi: 10.1016/j.neuron.2009.03.029. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [4].Santamaría D., Barrière C., Cerqueira A., Hunt S., Tardy C., Newton K., et al. Cdk1 is sufficient to drive the mammalian cell cycle. Nature. 2007;448:811–816. doi: 10.1038/nature06046. [DOI] [PubMed] [Google Scholar]
  • [5].Sudakin V., Ganoth D., Dahan A., Heller H., Hershko J., Luca F.C., et al. The cyclosome, a large complex containing cyclin-selective ubiquitin ligase activity, targets cyclins for destruction at the end of mitosis. Mol Biol Cell. 1995;6:185–197. doi: 10.1091/mbc.6.2.185. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [6].Vodermaier H.C. APC/C and SCF: controlling each other and the cell cycle. Curr Biol. 2004;14:R787–796. doi: 10.1016/j.cub.2004.09.020. [DOI] [PubMed] [Google Scholar]
  • [7].Dai Y., Grant S. Cyclin-dependent kinase inhibitors. Curr Opin Pharmacol. 2003;3:362–370. doi: 10.1016/S1471-4892(03)00079-1. [DOI] [PubMed] [Google Scholar]
  • [8].Meijer L., Raymond E. Roscovitine and other purines as kinase inhibitors. From starfish oocytes to clinical trials. Acc Chem Res. 2003;36:417–425. doi: 10.1021/ar0201198. [DOI] [PubMed] [Google Scholar]
  • [9].Bach S., Knockaert M., Reinhardt J., Lozach O., Schmitt S., Baratte B., et al. Roscovitine targets, protein kinases and pyridoxal kinase. J Biol Chem. 2005;280:31208–31219. doi: 10.1074/jbc.M500806200. [DOI] [PubMed] [Google Scholar]
  • [10].Herrup K., Busser J.C. The induction of multiple cell cycle events precedes target-related neuronal death. Development. 1995;121:2385–2395. doi: 10.1242/dev.121.8.2385. [DOI] [PubMed] [Google Scholar]
  • [11].Hernández-Ortega K., Ferrera P., Arias C. Sequential expression of cell-cycle regulators and Alzheimer’s disease-related proteins in entorhinal cortex after hippocampal excitotoxic damage. J Neurosci Res. 2007;85:1744–1751. doi: 10.1002/jnr.21301. [DOI] [PubMed] [Google Scholar]
  • [12].Park D.S., Morris E.J., Padmanabban J., Shelanski M.L., Geller H.M., Greene L.A. Cyclin dependent kinases participate in death of neurons evoked by DNA-damaging agents. J Cell Biol. 1998;143:457–467. doi: 10.1083/jcb.143.2.457. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [13].Verdaguer E., García-Jordà E., Canudas A.M., Domínguez E., Jiménez A., Pubill D., et al. Kainic acid-induced apoptosis in cerebellar granule neurons: an attempt at cell cycle re-entry. Neuroreport. 2002;13:413–416. doi: 10.1097/00001756-200203250-00010. [DOI] [PubMed] [Google Scholar]
  • [14].Copani A., Condorelli F., Caruso A., Vancheri C., Sala A., Giuffrida Stella A.M., et al. Mitotic signaling by β-amyloid causes neuronal death. FASEB J. 1999;13:2225–2234. [PubMed] [Google Scholar]
  • [15].Giovanni A., Wirtz-Brugger F., Keramaris E., Slack R., Park D.S. Involment of cell cycle elements, cyclin dependent kinases, pRb, and E2FxDP, in β-amyloid induced neuronal death. J Biol Chem. 1999;274:19011–19016. doi: 10.1074/jbc.274.27.19011. [DOI] [PubMed] [Google Scholar]
  • [16].Bhaskar K., Miller M., Chludzinski A., Herrup K., Zagorski M., Lamb B.T. The PI3K-Akt-mTOR pathway regulates Aβ oligomer induced neuronal cell cycle events. Mol Neurodegener. 2009;4:14–31. doi: 10.1186/1750-1326-4-14. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [17].Hayashi T., Sakai K., Sasaki C., Zhang W.R., Abe K. Phosphorylation of retinoblastoma protein in rat brain after transient middle cerebral artery occlusion. Neuropathol Appl Neurobiol. 2000;26:390–397. doi: 10.1046/j.1365-2990.2000.00264.x. [DOI] [PubMed] [Google Scholar]
  • [18].Byrnes K.R., Faden A.I. Role of cell cycle proteins in CNS injury. Neurochem Res. 2007;32:1799–1807. doi: 10.1007/s11064-007-9312-2. [DOI] [PubMed] [Google Scholar]
  • [19].Nagy Z., Esiri M.M. Neuronal cyclin expression in the hippocampus in temporal lobe epilepsy. Exp Neurol. 1998;150:240–247. doi: 10.1006/exnr.1997.6753. [DOI] [PubMed] [Google Scholar]
  • [20].Rangathan S., Bowser S. Alterations in G1 to S phase cell cycle regulators during amyotrophic lateral sclerosis. Am J Pathol. 2003;162:823–835. doi: 10.1016/S0002-9440(10)63879-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [21].Jordan-Sciutto K.L., Dorsey R., Chalovich E.M., Hammond R.R., Achim C.L. Expression patterns of retinoblastoma protein in Parkinson disease. J Neuropathol Exp Neurol. 2003;62:68–74. doi: 10.1093/jnen/62.1.68. [DOI] [PubMed] [Google Scholar]
  • [22].Arendt T., Rödel L., Gärtner U., Holzer M. Expression of the cyclindependent kinase inhibitor p16 in Alzheimer’s disease. Neuroreport. 1996;7:3047–3049. doi: 10.1097/00001756-199611250-00050. [DOI] [PubMed] [Google Scholar]
  • [23].Nagy Z., Esiri M.M., Cato A.M., Smith A.D. Cell cycle markers in the hippocampus in Alzheimer’s disease. Acta Neuropathol (Berl) 1997;94:6–15. doi: 10.1007/s004010050665. [DOI] [PubMed] [Google Scholar]
  • [24].Vincent I., Jicha G., Rosado M., Dickson D. Aberrant expression of mitotic Cdc2/Cyclin B1 kinase in degenerating neurons of Alzheimer’s disease brain. J Neurosci. 1997;17:3588–3598. doi: 10.1523/JNEUROSCI.17-10-03588.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [25].Busser J., Geldmacher D.S., Herrup K. Ectopic cell cycle proteins predict the sites of neuronal death in Alzheimer’s disease brain. J Neurosci. 1998;18:2801–2807. doi: 10.1523/JNEUROSCI.18-08-02801.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [26].Raina A.K., Zhu X., Smith M.A. Alzheimer’s disease and the cell cycle. Acta Neurobiol Exp (Wars) 2004;64:107–112. doi: 10.55782/ane-2004-1496. [DOI] [PubMed] [Google Scholar]
  • [27].Copani A., Caraci F., Hoozemans J.J., Calafiore M., Sortino M.A., Nicoletti F. The nature of the cell cycle in neurons: focus on a “noncanonical” pathway of DNA replication causally related to death. Biochim Biophys Acta. 2007;1772:409–412. doi: 10.1016/j.bbadis.2006.10.016. [DOI] [PubMed] [Google Scholar]
  • [28].McShea A., Lee H.G., Petersen R.B., Casadesus G., Vincent I., Linford N.J., et al. Neuronal cell cycle re-entry mediates Alzheimer disease-type changes. Biochim Biophys Acta. 2007;1772:467–472. doi: 10.1016/j.bbadis.2006.09.010. [DOI] [PubMed] [Google Scholar]
  • [29].Nagy Z. The dysregulation of the cell cycle and the diagnosis of Alzheimer’s disease. Biochim Biophys Acta. 2007;1772:402–408. doi: 10.1016/j.bbadis.2006.11.001. [DOI] [PubMed] [Google Scholar]
  • [30].Zekanowski C., Wojda U. Aneuploidy, chromosomal missegregation, and cell cycle reentry in Alzheimer’s disease. Acta Neurobiol Exp (Wars) 2009;69:232–253. doi: 10.55782/ane-2009-1748. [DOI] [PubMed] [Google Scholar]
  • [31].Lee E.Y., Chang C.Y., Hu N., Wang Y.C., Lai C.C., Herrup K., et al. Mice deficient for Rb are nonviable and show defects in neurogenesis and haematopoiesis. Nature. 1992;359:288–294. doi: 10.1038/359288a0. [DOI] [PubMed] [Google Scholar]
  • [32].Clarke A.R., Maandag E.R., van Roon M., van der Lugt N.M., van der Valk M., Hooper M.L., et al. Requirement for a functional Rb-1 gene in murine development. Nature. 1992;359:328–330. doi: 10.1038/359328a0. [DOI] [PubMed] [Google Scholar]
  • [33].Jacks T., Fazeli A., Schmitt E.M., Bronson R.T., Goodell M.A., Weinberg R.A. Effects of an Rb mutation in the mouse. Nature. 1992;359:295–300. doi: 10.1038/359295a0. [DOI] [PubMed] [Google Scholar]
  • [34].Liu D.X., Greene L.A. Neuronal apoptosis at the G1/S cell cycle checkpoint. Cell Tissue Res. 2001;305:217–228. doi: 10.1007/s004410100396. [DOI] [PubMed] [Google Scholar]
  • [35].Becker E.B.E., Bonni A. Cell cycle regulation of neuronal apoptosis in development and disease. Prog Neurobiol. 2004;72:1–25. doi: 10.1016/j.pneurobio.2003.12.005. [DOI] [PubMed] [Google Scholar]
  • [36].Tomashevski A., Webster D.R., Grammas P., Gorospe M., Kruman I.I. Cyclin-C-dependent cell-cycle entry is required for activation of non-homologous end joining DNA repair in postmitotic neurons. Cell Death Differ. 2010;17:1189–1198. doi: 10.1038/cdd.2009.221. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [37].Ajioka I., Martins R.A.P., Bayazitov I.T., Donovan S., Johnson D.A., Frase S., et al. Differentiated horizontal interneurons clonally expand to form metastatic retinoblastoma in mice. Cell. 2007;131:378–390. doi: 10.1016/j.cell.2007.09.036. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [38].Schmetsdorf S., Arnold E., Holzer M., Arendt T., Gärtner U. A putative role for cell cycle-related proteins in microtubule-based neuroplasticity. Eur J Neurosci. 2009;29:1096–1107. doi: 10.1111/j.1460-9568.2009.06661.x. [DOI] [PubMed] [Google Scholar]
  • [39].Schmetsdorf S., Gärtner U., Arendt T. Constitutive expression of functionally active cyclin-dependent kinases and their binding partners suggests noncanonical functions of cell cycle regulators in differentiated neurons. Cereb Cortex. 2007;17:1821–1829. doi: 10.1093/cercor/bhl091. [DOI] [PubMed] [Google Scholar]
  • [40].Arendt T. Synaptic degeneration in Alzheimer’s disease. Acta Neuropathol. 2009;118:167–179. doi: 10.1007/s00401-009-0536-x. [DOI] [PubMed] [Google Scholar]
  • [41].Chang F., Steelman L.S., McCubrey J.A. Raf-induced cell cycle progression in human TF-1 hematopoietic cells. Cell Cycle. 2002;1:220–226. doi: 10.4161/cc.1.3.128. [DOI] [PubMed] [Google Scholar]
  • [42].Sears R.C., Nevins J.R. Signaling networks that link cell proliferation and cell fate. J Biol Chem. 2002;277:11617–11620. doi: 10.1074/jbc.R100063200. [DOI] [PubMed] [Google Scholar]
  • [43].Arendt T., Gärtner U., Seeger G., Barmashenko G., Palm K., Mittmann T., et al. Neuronal activation of Ras regulates synaptic connectivity. Eur J Neurosci. 2004;19:2953–2966. doi: 10.1111/j.0953-816X.2004.03409.x. [DOI] [PubMed] [Google Scholar]
  • [44].Nakayama K.I., Nakayama K. Ubiquitin system regulating G1 and S phases of cell cycle. Tanpakushitsu Kakusan Koso. 2006;51:1362–1369. [PubMed] [Google Scholar]
  • [45].Kuczera T., Stilling R.M., Hsia H.E., Bahari-Javan S., Irniger S., Nasmyth K., et al. The anaphase promoting complex is required for memory function in mice. Learn Mem. 2010;18:49–57. doi: 10.1101/lm.1998411. [DOI] [PubMed] [Google Scholar]
  • [46].Konishi Y., Stegmüller J., Matsuda T., Bonni S., Bonni A. Cdh1-APC controls axonal growth and patterning in the mammalian brain. Science. 2004;303:1026–1030. doi: 10.1126/science.1093712. [DOI] [PubMed] [Google Scholar]
  • [47].Zhang J., Li H., Yabut O., Fitzpatrick H., D’Arcangelo G., Herrup K. Cdk5 suppresses the neuronal cell cycle by disrupting the E2F1-DP1 complex. J Neurosci. 2010;30:5219–5228. doi: 10.1523/JNEUROSCI.5628-09.2010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [48].Seeburg D.P., Feliu-Mojer M., Gaiottino J., Pak D.T., Sheng M. Critical role of CDK5 and Polo-like kinase 2 in homeostatic synaptic plasticity during elevated activity. Neuron. 2008;58:571–583. doi: 10.1016/j.neuron.2008.03.021. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [49].Greene L.A., Liu D.X., Troy C.M., Biswas S.C. Cell cycle molecules define a pathway required for neuron death in development and disease. Biochim Biophys Acta. 2007;1772:392–401. doi: 10.1016/j.bbadis.2006.12.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [50].Biswas S.C., Zhang Y., Iyirhiaro G., Willett R.T., Rodriguez Gonzalez Y., Cregan S.P., et al. Sertad1 plays an essential role in developmental and pathological neuron death. J Neurosci. 2010;30:3973–3982. doi: 10.1523/JNEUROSCI.6421-09.2010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [51].Zhang J., Li H., Herrup K. Cdk5 nuclear localization is p27-dependent in nerve cells: implications for cell cycle suppression and caspase-3 activation. J Biol Chem. 2010;285:14052–14061. doi: 10.1074/jbc.M109.068262. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [52].Park D.S., Morris E.J., Greene L.A., Geller H.M. G1/S cell cycle blockers and inhibitors of cyclin-dependent kinases suppress camptothecin-induced neuronal apoptosis. J Neurosci. 1997;17:1256–1270. doi: 10.1523/JNEUROSCI.17-04-01256.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [53].Osuga H., Osuga S., Wang F., Fetni R., Hogan M.J., Slack R.S., et al. Cyclin-dependent kinases as a therapeutic target for stroke. Proc Natl Acad Sci U S A. 2000;97:10254–10259. doi: 10.1073/pnas.170144197. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [54].Bates S., Phillips A.C., Clark P.A., Stott F., Peters G., Ludwig R.L., et al. p14ARF links the tumour suppressors RB and p53. Nature. 1998;395:124–125. doi: 10.1038/25867. [DOI] [PubMed] [Google Scholar]
  • [55].Moroni M.C., Hickman E.S., Lazzerini Denchi E., Caprara G., Colli E., et al. Apaf-1 is a transcriptional target for E2F and p53. Nat Cell Biol. 2001;3:552–558. doi: 10.1038/35078527. [DOI] [PubMed] [Google Scholar]
  • [56].Nahle Z., Polakoff J., Davuluri R.V., McCurrach M.E., Jacobson M.D., Narita M., et al. Direct coupling of the cell cycle and cell death machinery by E2F. Nat Cell Biol. 2002;4:859–864. doi: 10.1038/ncb868. [DOI] [PubMed] [Google Scholar]
  • [57].Konishi Y., Bonni A. The E2F-Cdc2 cell-cycle pathway specifically mediates activity deprivation-induced apoptosis of postmitotic neurons. J Neurosci. 2003;23:1649–1658. doi: 10.1523/JNEUROSCI.23-05-01649.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [58].Yuan Z., Becker E.B., Merlo P., Yamada T., DiBacco S., Konishi Y., et al. Activation of FOXO1 by Cdk1 in cycling cells and postmitotic neurons. Science. 2008;319:1665–1668. doi: 10.1126/science.1152337. [DOI] [PubMed] [Google Scholar]
  • [59].Konishi Y., Lehtinen M., Donovan N., Bonni A. Cdc2 phosphorylation of BAD links the cell cycle to the cell death machinery. Mol Cell. 2002;9:1005–1016. doi: 10.1016/S1097-2765(02)00524-5. [DOI] [PubMed] [Google Scholar]
  • [60].Freeman R.S., Estus S., Johnson E.M., Jr Analysis of cell cycle related gene expression in postmitotic neurons: selective induction of cyclin D1 during programmed cell death. Neuron. 1994;12:343–355. doi: 10.1016/0896-6273(94)90276-3. [DOI] [PubMed] [Google Scholar]
  • [61].Gao C.Y., Zalenka P.S. Induction of cyclin B and H1 kinase activity in apoptotic PC12 cells. Exp Cell Res. 1995;219:612–618. doi: 10.1006/excr.1995.1271. [DOI] [PubMed] [Google Scholar]
  • [62].Farinelli S.A., Greene L.A. Cell cycle blockers mimosine, ciclopirox, and derefoxamine prevent the death of PC12 cells and postmitotic sympathetic neurons after removal of trophic support. J Neurosci. 1996;16:1150–1162. doi: 10.1523/JNEUROSCI.16-03-01150.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [63].Hamilton B.A., Frankel W.N., Kerrebrok A.W., Hawkins T.L., FitzHugh W., Kusumi K., et al. Disruption of the nuclear hormone receptor RORα in staggerer mice. Nature. 1996;379:736–739. doi: 10.1038/379736a0. [DOI] [PubMed] [Google Scholar]
  • [64].Herrup K., Sunter K. Numerical matching during cerebellar development: quantitative analysis of granule cell death in staggerer mouse chimeras. J Neurosci. 1987;7:829–836. doi: 10.1523/JNEUROSCI.07-03-00829.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [65].Susuki T., Oishi M., Marshak D., Czernik A., Nairn A., Greengard P. Cell cycle-dependent regulation of the phosphorylation and metabolism of the Alzheimer amyloid precursor protein. EMBO J. 1994;13:1114–1122. doi: 10.1002/j.1460-2075.1994.tb06360.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [66].Nagy Z., Esiri M.M., Smith A.D. Expression of cell division markers in the hippocampus in Alzheimer’s disease and other neurodegenerative conditions. Acta Neuropathol. 1997;93:294–300. doi: 10.1007/s004010050617. [DOI] [PubMed] [Google Scholar]
  • [67].Lopes J.P., Blurton-Jones M., Yamasaki T.R., Agostinho P., LaFerla F.M. Activation of cell cycle proteins in transgenic mice in response to neuronal loss but not amyloid-β and tau pathology. J Alzheimers Dis. 2009;16:541–549. doi: 10.3233/JAD-2009-0993. [DOI] [PubMed] [Google Scholar]
  • [68].Lopes J.P., Oliveira C.R., Agostinho P. Neurodegeneration in an Aβ-induced model of Alzheimer’s disease: the role of Cdk5. Aging Cell. 2010;9:64–77. doi: 10.1111/j.1474-9726.2009.00536.x. [DOI] [PubMed] [Google Scholar]
  • [69].Yang Y., Geldmacher D.S., Herrup K. DNA replication precedes neuronal cell death in Alzheimer’s disease. J Neurosci. 2001;21:26661–26668. doi: 10.1523/JNEUROSCI.21-08-02661.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [70].Thomas P., Fenech M. Chromosome 17 and 21 aneuploidy in buccal cells is increased with ageing and in Alzheimer’s disease. Mutagenesis. 2008;23:57–65. doi: 10.1093/mutage/gem044. [DOI] [PubMed] [Google Scholar]
  • [71].Bonda D.J., Evans T.A., Santocanale C., Llosá J.C., Viña J., Bajic V.P., et al. Evidence for the progression through S-phase in the ectopic cell cycle re-entry of neurons in Alzheimer disease. Aging (Albany NY) 2009;1:382–388. doi: 10.18632/aging.100044. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [72].Raina A.K., Zhu X., Rottkamp C.A., Monteiro M., Takeda A., Smith M.A. Cyclin’ toward dementia: cell cycle abnormalities and abortive oncogenesis in Alzheimer disease. J Neurosci Res. 2000;61:128–133. doi: 10.1002/1097-4547(20000715)61:2<128::AID-JNR2>3.0.CO;2-H. [DOI] [PubMed] [Google Scholar]
  • [73].Zhu X., Siedlak S.L., Wang Y., Perry G., Castellani R.J., Cohen M.L., et al. Neuronal binucleation in Alzheimer disease hippocampus. Neuropathol Appl Neurobiol. 2008;34:457–465. doi: 10.1111/j.1365-2990.2007.00908.x. [DOI] [PubMed] [Google Scholar]
  • [74].Pei J.J., Braak H., Gong C.X., Grundke-Iqbal I., Iqbal K., Winblad B., et al. Up-regulation of cell division cycle (cdc) 2 kinase in neurons with early stage Alzheimer’s disease neurofibrillary degeneration. Acta Neuropathol. 2002;104:369–376. doi: 10.1007/s00401-002-0565-1. [DOI] [PubMed] [Google Scholar]
  • [75].Currais A., Hortobágyi T., Soriano S. The neuronal cell cycle as a mechanism of pathogenesis in Alzheimer’s disease. Aging (Albany NY) 2009;1:363–371. doi: 10.18632/aging.100045. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [76].Arendt T. Neurodegeneration and plasticity. Int J Dev Neurosci. 2004;22:507–514. doi: 10.1016/j.ijdevneu.2004.07.007. [DOI] [PubMed] [Google Scholar]
  • [77].Arendt T., Brückner M.K. Linking cell-cycle dysfunction in Alzheimer’s disease to a failure of synaptic plasticity. Biochim Biophys Acta. 2007;1772:413–421. doi: 10.1016/j.bbadis.2006.12.005. [DOI] [PubMed] [Google Scholar]
  • [78].Rashidian J., Iyirhiaro G., Aleyasin H., Rios M., Vincent I., Callaghan S., et al. Multiple cyclin-dependent kinases signals are critical mediators of ischemia/hypoxic neuronal death in vitro and in vivo. Proc Natl Acad Sci U S A. 2005;102:14080–14085. doi: 10.1073/pnas.0500099102. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [79].Höglinger G.U., Breunig J.J., Depboylu C., Rouaux C., Michel P.P., Alvarez-Fischer D., et al. The pRb/E2F cell-cycle pathway mediates cell death in Parkinson’s disease. Proc Natl Acad Sci U S A. 2007;104:3585–3590. doi: 10.1073/pnas.0611671104. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [80].Staropoli J.F., McDermott C., Martinat C., Schulman B., Demireva E., Abeliovich A. Parkin is a component of an SCF-like ubiquitin ligase complex and protects postmitotic neurons from kainate excitotoxicity. Neuron. 2003;37:735–749. doi: 10.1016/S0896-6273(03)00084-9. [DOI] [PubMed] [Google Scholar]
  • [81].West A.B., Dawson V.L., Dawsona T.M. To die or grow: Parkinson’s disease and cancer. Trends Neurosci. 2005;28:348–352. doi: 10.1016/j.tins.2005.05.002. [DOI] [PubMed] [Google Scholar]
  • [82].El-Khodor B.F., Oo T.F., Kholodilov N., Burke R.E. Ectopic expression of cell cycle markers in models of induced programmed cell death in dopamine neurons of the rat substantia nigra pars compacta. Exp Neurol. 2003;179:17–27. doi: 10.1006/exnr.2002.8047. [DOI] [PubMed] [Google Scholar]
  • [83].Rodriguez-Blanco J., Martín V., Herrera F., García-Santos G., Antolín I., Rodriguez C. Intracellular signaling pathways involved in post-mitotic dopaminergic PC12 cell death induced by 6-hydroxydopamine. J Neurochem. 2008;107:127–140. doi: 10.1111/j.1471-4159.2008.05588.x. [DOI] [PubMed] [Google Scholar]
  • [84].Smith P.D., Crocker S.J., Jackson-Lewis V., Jordan-Sciutto K.L., Hayley S., Mount M.P., et al. Cyclin-dependent kinase 5 is a mediator of dopaminergic neuron loss in a mouse model of Parkinson’s disease. Proc Natl Acad Sci U S A. 2003;100:13650–13655. doi: 10.1073/pnas.2232515100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [85].Nguyen M.D., Boudreau M., Kriz J., Couillard-Despres S., Kaplan D.R., Julien J.P. Cell cycle regulators in the neuronal death pathway of amyotrophic lateral sclerosis caused by mutant superoxide dismutase 1. J Neurosci. 2003;23:2131–2140. doi: 10.1523/JNEUROSCI.23-06-02131.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [86].Ferraiuolo L., Heath P.R., Holden H., Kasher P., Kirby J., Shaw P.J. Microarray analysis of the cellular pathways involved in the adaptation to and progression of motor neuron injury in the SOD1 G93A mouse model of familial ALS. J Neurosci. 2007;27:9201–9219. doi: 10.1523/JNEUROSCI.1470-07.2007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [87].Pelegrí C., Duran-Vilaregut J., del Valle J., Crespo-Biel N., Ferrer I., Pallàs M., et al. Cell cycle activation in striatal neurons from Huntington’s disease patients and rats treated with 3-nitropropionic acid. Int J Dev Neurosci. 2008;26:665–671. doi: 10.1016/j.ijdevneu.2008.07.016. [DOI] [PubMed] [Google Scholar]
  • [88].Lee H.G., Casadesus G., Nunomura A., Zhu X., Castellani R.J., Richardson S.L., et al. The neuronal expression of MYC causes a neurodegenerative phenotype in a novel transgenic mouse. Am J Pathol. 2009;174:891–897. doi: 10.2353/ajpath.2009.080583. [DOI] [PMC free article] [PubMed] [Google Scholar]

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