Targeting Cdk5 Activity in Neuronal Degeneration and Regeneration

  • Jyotshnabala Kanungo
  • Ya-li Zheng
  • Niranjana D. Amin
  • Harish C. PantEmail author
Review Paper


The major priming event in neurodegeneration is loss of neurons. Loss of neurons by apoptotic mechanisms is a theme for studies focused on determining therapeutic strategies. Neurons following an insult, activate a number of signal transduction pathways, of which, kinases are the leading members. Cyclin-dependent kinase 5 (Cdk5) is one of the kinases that have been linked to neurodegeneration. Cdk5 along with its principal activator p35 is involved in multiple cellular functions ranging from neuronal differentiation and migration to synaptic transmission. However, during neurotoxic stress, intracellular rise in Ca2+ activates calpain, which cleaves p35 to generate p25. The long half-life of Cdk5/p25 results in a hyperactive, aberrant Cdk5 that hyperphosphorylates Tau, neurofilament and other cytoskeletal proteins. These hyperphosphorylated cytoskeletal proteins set the groundwork to forming neurofibrillary tangles and aggregates of phosphorylated proteins, hallmarks of neurodegenerative diseases like Alzheimer’s disease, Parkinson’s disease and Amyotropic Lateral Sclerosis. Attempts to selectively target Cdk5/p25 activity without affecting Cdk5/p35 have been largely unsuccessful. A polypeptide inhibitor, CIP (Cdk5 inhibitory peptide), developed in our laboratory, successfully inhibits Cdk5/p25 activity in vitro, in cultured primary neurons, and is currently undergoing validation tests in mouse models of neurodegeneration. Here, we discuss the therapeutic potential of CIP in regenerating neurons that are exposed to neurodegenerative stimuli.


Cdk5 Neuron regeneration Tau Hyperphosphorylation Neurodegeneration 



This work was supported by intramural funds from the National Institute of Neurological Disorders and Stroke, National Institutes of Health.


  1. Ahlijanian MK, Barrezueta NX, Williams RD, Jakowski A, Kowsz KP, McCarthy S, Coskran T, Carlo A, Seymour PA, Burkhardt JE et al (2000) Hyperphosphorylated tau and neurofilament and cytoskeletal disruptions in mice overexpressing human p25, an activator of cdk5. Proc Natl Acad Sci USA 97:2910–2915. doi: 10.1073/pnas.040577797 CrossRefPubMedGoogle Scholar
  2. Alvarez A, Toro R, Caceres A, Maccioni RB (1999) Inhibition of tau phosphorylating protein kinase cdk5 prevents beta-amyloid-induced neuronal death. FEBS Lett 459:421–426. doi: 10.1016/S0014-5793(99)01279-X CrossRefPubMedGoogle Scholar
  3. Andorfer C, Acker CM, Kress Y, Hof PR, Duff K, Davies P (2005) Cell-cycle reentry and cell death in transgenic mice expressing nonmutant human tau isoforms. J Neurosci 25:5446–5454. doi: 10.1523/JNEUROSCI.4637-04.2005 CrossRefPubMedGoogle Scholar
  4. Angelo M, Plattner F, Giese KP (2006) Cyclin-dependent kinase 5 in synaptic plasticity, learning and memory. J Neurochem 99:353–370. doi: 10.1111/j.1471-4159.2006.04040.x CrossRefPubMedGoogle Scholar
  5. Apfel SC (2000) Neurotrophic factors and pain. Clin J Pain 16:S7–S11PubMedGoogle Scholar
  6. Chae T, Kwon YT, Bronson R, Dikkes P, Li E, Tsai LH (1997) Mice lacking p35, a neuronal specific activator of Cdk5, display cortical lamination defects, seizures, and adult lethality. Neuron 18:29–42. doi: 10.1016/S0896-6273(01)80044-1 CrossRefPubMedGoogle Scholar
  7. Cheung EC, Slack RS (2004) Emerging role for ERK as a key regulator of neuronal apoptosis. Sci STKE 2004:PE45. doi: 10.1126/stke.2512004pe45 CrossRefPubMedGoogle Scholar
  8. Cheung ZH, Gong K, Ip NY (2008) Cyclin-dependent kinase 5 supports neuronal survival through phosphorylation of Bcl-2. J Neurosci 28:4872–4877. doi: 10.1523/JNEUROSCI.0689-08.2008 CrossRefPubMedGoogle Scholar
  9. Cicero S, Herrup K (2005) Cyclin-dependent kinase 5 is essential for neuronal cell cycle arrest and differentiation. J Neurosci 25:9658–9668. doi: 10.1523/JNEUROSCI.1773-05.2005 CrossRefPubMedGoogle Scholar
  10. Crocker SJ, Liston P, Anisman H, Lee CJ, Smith PD, Earl N, Thompson CS, Park DS, Korneluk RG, Robertson GS (2003a) Attenuation of MPTP-induced neurotoxicity and behavioural impairment in NSE-XIAP transgenic mice. Neurobiol Dis 12:150–161. doi: 10.1016/S0969-9961(02)00020-7 CrossRefPubMedGoogle Scholar
  11. Crocker SJ, Smith PD, Jackson-Lewis V, Lamba WR, Hayley SP, Grimm E, Callaghan SM, Slack RS, Melloni E, Przedborski S et al (2003b) Inhibition of calpains prevents neuronal and behavioral deficits in an MPTP mouse model of Parkinson’s disease. J Neurosci 23:4081–4091PubMedGoogle Scholar
  12. Cruz JC, Tsai LH (2004) A Jekyll and Hyde kinase: roles for Cdk5 in brain development and disease. Curr Opin Neurobiol 14:390–394. doi: 10.1016/j.conb.2004.05.002 CrossRefPubMedGoogle Scholar
  13. Cruz JC, Tseng HC, Goldman JA, Shih H, Tsai LH (2003) Aberrant Cdk5 activation by p25 triggers pathological events leading to neurodegeneration and neurofibrillary tangles. Neuron 40:471–483. doi: 10.1016/S0896-6273(03)00627-5 CrossRefPubMedGoogle Scholar
  14. Cruz JC, Kim D, Moy LY, Dobbin MM, Sun X, Bronson RT, Tsai LH (2006) p25/cyclin-dependent kinase 5 induces production and intraneuronal accumulation of amyloid beta in vivo. J Neurosci 26:10536–10541. doi: 10.1523/JNEUROSCI.3133-06.2006 CrossRefPubMedGoogle Scholar
  15. Dhavan R, Tsai LH (2001) A decade of CDK5. Nat Rev Mol Cell Biol 2:749–759. doi: 10.1038/35096019 CrossRefPubMedGoogle Scholar
  16. Drewes G (2004) MARKing tau for tangles and toxicity. Trends Biochem Sci 29:548–555. doi: 10.1016/j.tibs.2004.08.001 CrossRefPubMedGoogle Scholar
  17. Fernandez JA, Rojo L, Kuljis RO, Maccioni RB (2008) The damage signals hypothesis of Alzheimer’s disease pathogenesis. J Alzheimers Dis 14:329–333PubMedGoogle Scholar
  18. Fischer A, Sananbenesi F, Spiess J, Radulovic J (2003) Cdk5: a novel role in learning and memory. Neurosignals 12:200–208. doi: 10.1159/000074621 CrossRefPubMedGoogle Scholar
  19. Fischer A, Sananbenesi F, Pang PT, Lu B, Tsai LH (2005) Opposing roles of transient and prolonged expression of p25 in synaptic plasticity and hippocampus-dependent memory. Neuron 48:825–838. doi: 10.1016/j.neuron.2005.10.033 CrossRefPubMedGoogle Scholar
  20. Gallo KA, Johnson GL (2002) Mixed-lineage kinase control of JNK and p38 MAPK pathways. Nat Rev Mol Cell Biol 3:663–672. doi: 10.1038/nrm906 CrossRefPubMedGoogle Scholar
  21. Geraerts M, Krylyshkina O, Debyser Z, Baekelandt V (2007) Concise review: therapeutic strategies for Parkinson disease based on the modulation of adult neurogenesis. Stem Cells 25:263–270. doi: 10.1634/stemcells.2006-0364 CrossRefPubMedGoogle Scholar
  22. Gross CG (2000) Neurogenesis in the adult brain: death of a dogma. Nat Rev Neurosci 1:67–73. doi: 10.1038/35036235 CrossRefPubMedGoogle Scholar
  23. Haass C, Selkoe DJ (2007) Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer’s amyloid beta-peptide. Nat Rev Mol Cell Biol 8:101–112. doi: 10.1038/nrm2101 CrossRefPubMedGoogle Scholar
  24. Hallows JL, Chen K, DePinho RA, Vincent I (2003) Decreased cyclin-dependent kinase 5 (cdk5) activity is accompanied by redistribution of cdk5 and cytoskeletal proteins and increased cytoskeletal protein phosphorylation in p35 null mice. J Neurosci 23:10633–10644PubMedGoogle Scholar
  25. Harada T, Morooka T, Ogawa S, Nishida E (2001) ERK induces p35, a neuron-specific activator of Cdk5, through induction of Egr1. Nat Cell Biol 3:453–459. doi: 10.1038/35074516 CrossRefPubMedGoogle Scholar
  26. Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297:353–356. doi: 10.1126/science.1072994 CrossRefPubMedGoogle Scholar
  27. Hashiguchi M, Saito T, Hisanaga S, Hashiguchi T (2002) Truncation of CDK5 activator p35 induces intensive phosphorylation of Ser202/Thr205 of human tau. J Biol Chem 277:44525–44530. doi: 10.1074/jbc.M207426200 CrossRefPubMedGoogle Scholar
  28. Heintz N (1993) Cell death and the cell cycle: a relationship between transformation and neurodegeneration? Trends Biochem Sci 18:157–159. doi: 10.1016/0968-0004(93)90103-T CrossRefPubMedGoogle Scholar
  29. Hooper NM, Turner AJ (2008) A new take on prions: preventing Alzheimer’s disease. Trends Biochem Sci 33:151–155. doi: 10.1016/j.tibs.2008.01.004 CrossRefPubMedGoogle Scholar
  30. Iijima K, Ando K, Takeda S, Satoh Y, Seki T, Itohara S, Greengard P, Kirino Y, Nairn AC, Suzuki T (2000) Neuron-specific phosphorylation of Alzheimer’s beta-amyloid precursor protein by cyclin-dependent kinase 5. J Neurochem 75:1085–1091. doi: 10.1046/j.1471-4159.2000.0751085.x CrossRefPubMedGoogle Scholar
  31. Imahori K, Uchida T (1997) Physiology and pathology of tau protein kinases in relation to Alzheimer’s disease. J Biochem 121:179–188PubMedGoogle Scholar
  32. Ishizawa T, Sahara N, Ishiguro K, Kersh J, McGowan E, Lewis J, Hutton M, Dickson DW, Yen SH (2003) Co-localization of glycogen synthase kinase-3 with neurofibrillary tangles and granulovacuolar degeneration in transgenic mice. Am J Pathol 163:1057–1067PubMedGoogle Scholar
  33. Johnson GV, Stoothoff WH (2004) Tau phosphorylation in neuronal cell function and dysfunction. J Cell Sci 117:5721–5729. doi: 10.1242/jcs.01558 CrossRefPubMedGoogle Scholar
  34. Kesavapany S, Lau KF, Ackerley S, Banner SJ, Shemilt SJ, Cooper JD, Leigh PN, Shaw CE, McLoughlin DM, Miller CC (2003) Identification of a novel, membrane-associated neuronal kinase, cyclin-dependent kinase 5/p35-regulated kinase. J Neurosci 23:4975–4983PubMedGoogle Scholar
  35. Kesavapany S, Amin N, Zheng YL, Nijhara R, Jaffe H, Sihag R, Gutkind JS, Takahashi S, Kulkarni A, Grant P, Pant HC (2004) p35/cyclin-dependent kinase 5 phosphorylation of ras guanine nucleotide releasing factor 2 (RasGRF2) mediates Rac-dependent Extracellular Signal-regulated kinase 1/2 activity, altering RasGRF2 and microtubule-associated protein 1b distribution in neurons. J Neurosci 24:4421–4431. doi: 10.1523/JNEUROSCI.0690-04.2004 CrossRefPubMedGoogle Scholar
  36. Kesavapany S, Pareek TK, Zheng YL, Amin N, Gutkind JS, Ma W, Kulkarni AB, Grant P, Pant HC (2006) Neuronal nuclear organization is controlled by cyclin-dependent kinase 5 phosphorylation of Ras Guanine nucleotide releasing factor-1. Neurosignals 15:157–173. doi: 10.1159/000095130 CrossRefPubMedGoogle Scholar
  37. Kesavapany S, Patel V, Zheng YL, Pareek TK, Bjelogrlic M, Albers W, Amin N, Jaffe H, Gutkind JS, Strong MJ et al (2007) Inhibition of Pin1 reduces glutamate-induced perikaryal accumulation of phosphorylated neurofilament-H in neurons. Mol Biol Cell 18:3645–3655. doi: 10.1091/mbc.E07-03-0237 CrossRefPubMedGoogle Scholar
  38. Ko J, Humbert S, Bronson RT, Takahashi S, Kulkarni AB, Li E, Tsai LH (2001) p35 and p39 are essential for cyclin-dependent kinase 5 function during neurodevelopment. J Neurosci 21:6758–6771PubMedGoogle Scholar
  39. Lee MS, Kwon YT, Li M, Peng J, Friedlander RM, Tsai LH (2000) Neurotoxicity induces cleavage of p35 to p25 by calpain. Nature 405:360–364. doi: 10.1038/35012636 CrossRefPubMedGoogle Scholar
  40. Li M, Ona VO, Guegan C, Chen M, Jackson-Lewis V, Andrews LJ, Olszewski AJ, Stieg PE, Lee JP, Przedborski S, Friedlander RM (2000) Functional role of caspase-1 and caspase-3 in an ALS transgenic mouse model. Science 288:335–339. doi: 10.1126/science.288.5464.335 CrossRefPubMedGoogle Scholar
  41. Li Y, Liu L, Barger SW, Griffin WS (2003) Interleukin-1 mediates pathological effects of microglia on tau phosphorylation and on synaptophysin synthesis in cortical neurons through a p38-MAPK pathway. J Neurosci 23:1605–1611PubMedGoogle Scholar
  42. Maccioni RB, Munoz JP, Barbeito L (2001) The molecular bases of Alzheimer’s disease and other neurodegenerative disorders. Arch Med Res 32:367–381. doi: 10.1016/S0188-4409(01)00316-2 CrossRefPubMedGoogle Scholar
  43. McShea A, Lee HG, Petersen RB, Casadesus G, Vincent I, Linford NJ, Funk JO, Shapiro RA, Smith MA (2007) Neuronal cell cycle re-entry mediates Alzheimer disease-type changes. Biochim Biophys Acta 1772:467–472PubMedGoogle Scholar
  44. Meyerson M, Enders GH, Wu CL, Su LK, Gorka C, Nelson C, Harlow E, Tsai LH (1992) A family of human cdc2-related protein kinases. EMBO J 11:2909–2917PubMedGoogle Scholar
  45. Morfini G, Szebenyi G, Elluru R, Ratner N, Brady ST (2002) Glycogen synthase kinase 3 phosphorylates kinesin light chains and negatively regulates kinesin-based motility. EMBO J 21:281–293. doi: 10.1093/emboj/21.3.281 CrossRefPubMedGoogle Scholar
  46. Morfini G, Szebenyi G, Brown H, Pant HC, Pigino G, DeBoer S, Beffert U, Brady ST (2004) A novel CDK5-dependent pathway for regulating GSK3 activity and kinesin-driven motility in neurons. EMBO J 23:2235–2245CrossRefPubMedGoogle Scholar
  47. Morita N, Kiryu S, Kiyama H (1996) p53-independent cyclin G expression in a group of mature neurons and its enhanced expression during nerve regeneration. J Neurosci 16:5961–5966PubMedGoogle Scholar
  48. Nagy Z (2000) Cell cycle regulatory failure in neurones: causes and consequences. Neurobiol Aging 21:761–769. doi: 10.1016/S0197-4580(00)00223-2 CrossRefPubMedGoogle Scholar
  49. Naska S, Park KJ, Hannigan GE, Dedhar S, Miller FD, Kaplan DR (2006) An essential role for the integrin-linked kinase-glycogen synthase kinase-3 beta pathway during dendrite initiation and growth. J Neurosci 26:13344–13356. doi: 10.1523/JNEUROSCI.4462-06.2006 CrossRefPubMedGoogle Scholar
  50. Nguyen MD, Mushynski WE, Julien JP (2002) Cycling at the interface between neurodevelopment and neurodegeneration. Cell Death Differ 9:1294–1306. doi: 10.1038/sj.cdd.4401108 CrossRefPubMedGoogle Scholar
  51. Ohshima T, Ward JM, Huh CG, Longenecker G, Veeranna, Pant HC, Brady RO, Martin LJ, Kulkarni AB (1996) Targeted disruption of the cyclin-dependent kinase 5 gene results in abnormal corticogenesis, neuronal pathology and perinatal death. Proc Natl Acad Sci USA 93:11173–11178. doi: 10.1073/pnas.93.20.11173 CrossRefPubMedGoogle Scholar
  52. Ojala JO, Sutinen EM, Salminen A, Pirttila T (2008) Interleukin-18 increases expression of kinases involved in tau phosphorylation in SH-SY5Y neuroblastoma cells. J Neuroimmunol 205:86–93. doi: 10.1016/j.jneuroim.2008.09.012 CrossRefPubMedGoogle Scholar
  53. Okamoto K, Beach D (1994) Cyclin G is a transcriptional target of the p53 tumor suppressor protein. EMBO J 13:4816–4822PubMedGoogle Scholar
  54. Otth C, Concha II, Arendt T, Stieler J, Schliebs R, Gonzalez-Billault C, Maccioni RB (2002) AbetaPP induces cdk5-dependent tau hyperphosphorylation in transgenic mice Tg2576. J Alzheimers Dis 4:417–430PubMedGoogle Scholar
  55. Patrick GN, Zukerberg L, Nikolic M, de la Monte S, Dikkes P, Tsai LH (1999) Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration. Nature 402:615–622. doi: 10.1038/45159 CrossRefPubMedGoogle Scholar
  56. Patzke H, Tsai LH (2002) Calpain-mediated cleavage of the cyclin-dependent kinase-5 activator p39 to p29. J Biol Chem 277:8054–8060. doi: 10.1074/jbc.M109645200 CrossRefPubMedGoogle Scholar
  57. Phiel CJ, Wilson CA, Lee VM, Klein PS (2003) GSK-3alpha regulates production of Alzheimer’s disease amyloid-beta peptides. Nature 423:435–439. doi: 10.1038/nature01640 CrossRefPubMedGoogle Scholar
  58. Quintanilla RA, Orellana DI, Gonzalez-Billault C, Maccioni RB (2004) Interleukin-6 induces Alzheimer-type phosphorylation of tau protein by deregulating the cdk5/p35 pathway. Exp Cell Res 295:245–257. doi: 10.1016/j.yexcr.2004.01.002 CrossRefPubMedGoogle Scholar
  59. Rojo LE, Fernandez JA, Maccioni AA, Jimenez JM, Maccioni RB (2008) Neuroinflammation: implications for the pathogenesis and molecular diagnosis of Alzheimer’s disease. Arch Med Res 39:1–16. doi: 10.1016/j.arcmed.2007.10.001 CrossRefPubMedGoogle Scholar
  60. Rudrabhatla P, Zheng YL, Amin ND, Kesavapany S, Albers W, Pant HC (2008) Pin1-dependent prolyl isomerization modulates the stress-induced phosphorylation of high molecular weight neurofilament protein. J Biol Chem 283:26737–26747. doi: 10.1074/jbc.M801633200 CrossRefPubMedGoogle Scholar
  61. Sato H, Nishimoto I, Matsuoka M (2002) Ik3–2, a relative to ik3–1/cables, is associated with cdk3, cdk5, and c-abl. Biochim Biophys Acta 1574:157–163PubMedGoogle Scholar
  62. Shan X, Chi L, Bishop M, Luo C, Lien L, Zhang Z, Liu R (2006) Enhanced de novo neurogenesis and dopaminergic neurogenesis in the substantia nigra of 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine-induced Parkinson’s disease-like mice. Stem Cells 24:1280–1287. doi: 10.1634/stemcells.2005-0487 CrossRefPubMedGoogle Scholar
  63. Sharma P, Veeranna, Sharma M, Amin ND, Sihag RK, Grant P, Ahn N, Kulkarni AB, Pant HC (2002) Phosphorylation of MEK1 by cdk5/p35 down-regulates the mitogen-activated protein kinase pathway. J Biol Chem 277:528–534. doi: 10.1074/jbc.M109324200 CrossRefPubMedGoogle Scholar
  64. Shelton SB, Johnson GV (2004) Cyclin-dependent kinase-5 in neurodegeneration. J Neurochem 88:1313–1326PubMedGoogle Scholar
  65. Shetty KT, Link WT, Pant HC (1993) Cdc2-like kinase from rat spinal cord specifically phosphorylates KSPXK motifs in neurofilament proteins: isolation and characterization. Proc Natl Acad Sci USA 90:6844–6848. doi: 10.1073/pnas.90.14.6844 CrossRefPubMedGoogle Scholar
  66. Slevin M, Krupinski J (2008) Cyclin-dependent kinase-5 targeting for ischaemic stroke. Curr Opin Pharmacol 9:119–124CrossRefPubMedGoogle Scholar
  67. Sultana R, Butterfield DA (2007) Regional expression of key cell cycle proteins in brain from subjects with amnestic mild cognitive impairment. Neurochem Res 32:655–662. doi: 10.1007/s11064-006-9123-x CrossRefPubMedGoogle Scholar
  68. Sun KH, de Pablo Y, Vincent F, Johnson EO, Chavers AK, Shah K (2008) Novel genetic tools reveal Cdk5’s major role in golgi fragmentation in Alzheimer’s disease. Mol Biol Cell 19:3052–3069. doi: 10.1091/mbc.E07-11-1106 CrossRefPubMedGoogle Scholar
  69. Takahashi S, Saito T, Hisanaga S, Pant HC, Kulkarni AB (2003) Tau phosphorylation by cyclin-dependent kinase 5/p39 during brain development reduces its affinity for microtubules. J Biol Chem 278:10506–10515. doi: 10.1074/jbc.M211964200 CrossRefPubMedGoogle Scholar
  70. Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS, Jones JM (1998) Embryonic stem cell lines derived from human blastocysts. Science 282:1145–1147. doi: 10.1126/science.282.5391.1145 CrossRefPubMedGoogle Scholar
  71. Town T, Zolton J, Shaffner R, Schnell B, Crescentini R, Wu Y, Zeng J, DelleDonne A, Obregon D, Tan J, Mullan M (2002) p35/Cdk5 pathway mediates soluble amyloid-beta peptide-induced tau phosphorylation in vitro. J Neurosci Res 69:362–372. doi: 10.1002/jnr.10299 CrossRefPubMedGoogle Scholar
  72. Van den Haute C, Spittaels K, Van Dorpe J, Lasrado R, Vandezande K, Laenen I, Geerts H, Van Leuven F (2001) Coexpression of human cdk5 and its activator p35 with human protein tau in neurons in brain of triple transgenic mice. Neurobiol Dis 8:32–44. doi: 10.1006/nbdi.2000.0333 CrossRefPubMedGoogle Scholar
  73. Voigt B, Krug M, Schachtele C, Totzke F, Hilgeroth A (2008) Probing novel 1-aza-9-oxafluorenes as selective GSK-3beta inhibitors. ChemMedChem 3:120–126. doi: 10.1002/cmdc.200700175 CrossRefPubMedGoogle Scholar
  74. Wang CX, Song JH, Song DK, Yong VW, Shuaib A, Hao C (2006) Cyclin-dependent kinase-5 prevents neuronal apoptosis through ERK-mediated upregulation of Bcl-2. Cell Death Differ 13:1203–1212. doi: 10.1038/sj.cdd.4401804 CrossRefPubMedGoogle Scholar
  75. Wen Y, Yang SH, Liu R, Perez EJ, Brun-Zinkernagel AM, Koulen P, Simpkins JW (2007) Cdk5 is involved in NFT-like tauopathy induced by transient cerebral ischemia in female rats. Biochim Biophys Acta 1772:473–483PubMedGoogle Scholar
  76. Yang Z, Zhu Q, Luo K, Zhou Q (2001) The 7SK small nuclear RNA inhibits the CDK9/cyclin T1 kinase to control transcription. Nature 414:317–322. doi: 10.1038/35104575 CrossRefPubMedGoogle Scholar
  77. Yang L, Sugama S, Mischak RP, Kiaei M, Bizat N, Brouillet E, Joh TH, Beal MF (2004) A novel systemically active caspase inhibitor attenuates the toxicities of MPTP, malonate, and 3NP in vivo. Neurobiol Dis 17:250–259. doi: 10.1016/j.nbd.2004.07.021 CrossRefPubMedGoogle Scholar
  78. Yoshimi K, Ren YR, Seki T, Yamada M, Ooizumi H, Onodera M, Saito Y, Murayama S, Okano H, Mizuno Y, Mochizuki H (2005) Possibility for neurogenesis in substantia nigra of parkinsonian brain. Ann Neurol 58:31–40. doi: 10.1002/ana.20506 CrossRefPubMedGoogle Scholar
  79. Yuan J, Yankner BA (2000) Apoptosis in the nervous system. Nature 407:802–809. doi: 10.1038/35037739 CrossRefPubMedGoogle Scholar
  80. Zauberman A, Lupo A, Oren M (1995) Identification of p53 target genes through immune selection of genomic DNA: the cyclin G gene contains two distinct p53 binding sites. Oncogene 10:2361–2366PubMedGoogle Scholar
  81. Zhao M, Momma S, Delfani K, Carlen M, Cassidy RM, Johansson CB, Brismar H, Shupliakov O, Frisen J, Janson AM (2003) Evidence for neurogenesis in the adult mammalian substantia nigra. Proc Natl Acad Sci USA 100:7925–7930. doi: 10.1073/pnas.1131955100 CrossRefPubMedGoogle Scholar
  82. Zhao C, Deng W, Gage FH (2008) Mechanisms and functional implications of adult neurogenesis. Cell 132:645–660. doi: 10.1016/j.cell.2008.01.033 CrossRefPubMedGoogle Scholar
  83. Zheng YL, Li BS, Amin ND, Albers W, Pant HC (2002) A peptide derived from cyclin-dependent kinase activator (p35) specifically inhibits Cdk5 activity and phosphorylation of tau protein in transfected cells. Eur J Biochem 269:4427–4434. doi: 10.1046/j.1432-1033.2002.03133.x CrossRefPubMedGoogle Scholar
  84. Zheng YL, Kesavapany S, Gravell M, Hamilton RS, Schubert M, Amin N, Albers W, Grant P, Pant HC (2005) A Cdk5 inhibitory peptide reduces tau hyperphosphorylation and apoptosis in neurons. EMBO J 24:209–220. doi: 10.1038/sj.emboj.7600441 CrossRefPubMedGoogle Scholar
  85. Zheng YL, Li BS, Kanungo J, Kesavapany S, Amin N, Grant P, Pant HC (2007) Cdk5 Modulation of mitogen-activated protein kinase signaling regulates neuronal survival. Mol Biol Cell 18:404–413. doi: 10.1091/mbc.E06-09-0851 CrossRefPubMedGoogle Scholar
  86. Zhu Z, Zhang Q, Yu Z, Zhang L, Tian D, Zhu S, Bu B, Xie M, Wang W (2007) Inhibiting cell cycle progression reduces reactive astrogliosis initiated by scratch injury in vitro and by cerebral ischemia in vivo. Glia 55:546–558. doi: 10.1002/glia.20476 CrossRefPubMedGoogle Scholar

Copyright information

© National Institutes of Health 2009

Authors and Affiliations

  • Jyotshnabala Kanungo
    • 1
  • Ya-li Zheng
    • 1
  • Niranjana D. Amin
    • 1
  • Harish C. Pant
    • 1
    Email author
  1. 1.Laboratory of Neurochemistry, National Institute of Neurological Disorders and StrokeNational Institutes of HealthBethesdaUSA

Personalised recommendations