Phosphorylation of collapsin response mediator protein-2 disrupts neuronal maturation in a model of adult neurogenesis: Implications for neurodegenerative disorders

Molecular Neurodegeneration

Eliezer Masliah³  Edward Rockenstein²  Cristian L Achim¹  Margarita Trejo-Morales²  Wilmar Dumaop³  Christina Patrick²  Rebecca Ruf²  Leslie Crews² 

[1] Department of Psychiatry; University of California, San Diego; 9500 Gilman Drive, La Jolla, CA 92093, USA;Department of Neurosciences; University of California, San Diego; 9500 Gilman Drive, La Jolla, CA 92093-0624, USA;Department of Pathology; University of California, San Diego; 9500 Gilman Drive, La Jolla, CA 92093, USA

关键词: neurite outgrowth;    microtubules;    CDK5;    dpysl2;    CRMP2;    encephalitis;    HIV;    neurogenesis;   

Others  :  865594
DOI  :  10.1186/1750-1326-6-67

 received in 2011-04-15, accepted in 2011-09-24,  发布年份 2011

【 摘 要 】

Background

Recent studies suggest that the pathogenic process in neurodegenerative disorders may disrupt mature neuronal circuitries and neurogenesis in the adult brain. Abnormal activation of CDK5 is associated with neurodegenerative disorders, and recently a critical role for CDK5 in adult neurogenesis has been identified. We have developed an in vitro model of abnormal CDK5 activation during adult hippocampal neurogenesis, and here we used this model to investigate aberrantly phosphorylated downstream targets of CDK5.

Results

Abnormal CDK5 activation in an in vitro model of adult neurogenesis results in hyperphosphorylation of collapsin-response mediator protein-2 (CRMP2) and impaired neurite outgrowth. Inhibition of CDK5, or expression of a non-phosphorylatable (S522A) CRMP2 construct reduced CRMP2 hyperphosphorylation, and reversed neurite outgrowth deficits. CRMP2 plays a role in microtubule dynamics; therefore we examined the integrity of microtubules in this model using biochemical and electron microscopy techniques. We found that microtubule organization was disrupted under conditions of CDK5 activation. Finally, to study the relevance of these findings to neurogenesis in neurodegenerative conditions associated with HIV infection, we performed immunochemical analyses of the brains of patients with HIV and transgenic mice expressing HIV-gp120 protein. CDK5-mediated CRMP2 phosphorylation was significantly increased in the hippocampus of patients with HIV encephalitis and in gp120 transgenic mice, and this effect was rescued by genetic down-modulation of CDK5 in the mouse model.

Conclusions

These results reveal a functional mechanism involving microtubule destabilization through which abnormal CDK5 activation and CRMP2 hyperphosphorylation might contribute to defective neurogenesis in neurodegenerative disorders such as HIV encephalitis.

【 授权许可】

   
2011 Crews et al; licensee BioMed Central Ltd.

【 图 表 】

【 参考文献 】

• [1]Lee HG, Moreira PI, Zhu X, Smith MA, Perry G: Staying connected: synapses in Alzheimer disease. Am J Pathol 2004, 165:1461-1464.
• [2]Masliah E, Heaton RK, Marcotte TD, Ellis RJ, Wiley CA, Mallory M, Achim CL, McCutchan JA, Nelson JA, Atkinson JH, Grant I: Dendritic injury is a pathological substrate for human immunodeficiency virus-related cognitive disorders. HNRC Group. The HIV Neurobehavioral Research Center. Ann Neurol 1997, 42:963-972.
• [3]Kaul M, Garden GA, Lipton SA: Pathways to neuronal injury and apoptosis in HIV-associated dementia. Nature 2001, 410:988-994.
• [4]Liu F, Su Y, Li B, Zhou Y, Ryder J, Gonzalez-DeWhitt P, May PC, Ni B: Regulation of amyloid precursor protein (APP) phosphorylation and processing by p35/Cdk5 and p25/Cdk5. FEBS Lett 2003, 547:193-196.
• [5]Patrick GN, Zukerberg L, Nikolic M, de la Monte S, Dikkes P, Tsai LH: Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration. Nature 1999, 402:615-622.
• [6]Wang GR, Shi S, Gao C, Zhang BY, Tian C, Dong CF, Zhou RM, Li XL, Chen C, Han J, Dong XP: Changes of tau profiles in brains of the hamsters infected with scrapie strains 263 K or 139 A possibly associated with the alteration of phosphate kinases. BMC Infect Dis 2010, 10:86. BioMed Central Full Text
• [7]Lee KY, Clark AW, Rosales JL, Chapman K, Fung T, Johnston RN: Elevated neuronal Cdc2-like kinase activity in the Alzheimer disease brain. Neurosci Res 1999, 34:21-29.
• [8]Patrick C, Crews L, Desplats P, Dumaop W, Rockenstein E, Achim CL, Everall IP, Masliah E: Increased CDK5 Expression in HIV Encephalitis Contributes to Neurodegeneration via Tau Phosphorylation and Is Reversed with Roscovitine. Am J Pathol 2011, 178:1646-1661.
• [9]Jin K, Peel AL, Mao XO, Xie L, Cottrell BA, Henshall DC, Greenberg DA: Increased hippocampal neurogenesis in Alzheimer's disease. Proc Natl Acad Sci USA 2004, 101:343-347.
• [10]Boekhoorn K, Joels M, Lucassen PJ: Increased proliferation reflects glial and vascular-associated changes, but not neurogenesis in the presenile Alzheimer hippocampus. Neurobiol Dis 2006, 24:1-14.
• [11]Li B, Yamamori H, Tatebayashi Y, Shafit-Zagardo B, Tanimukai H, Chen S, Iqbal K, Grundke-Iqbal I: Failure of neuronal maturation in Alzheimer disease dentate gyrus. J Neuropathol Exp Neurol 2008, 67:78-84.
• [12]Crews L, Adame A, Patrick C, Delaney A, Pham E, Rockenstein E, Hansen L, Masliah E: Increased BMP6 levels in the brains of Alzheimer's disease patients and APP transgenic mice are accompanied by impaired neurogenesis. J Neurosci 2010, 30:12252-12262.
• [13]Okamoto S, Kang YJ, Brechtel CW, Siviglia E, Russo R, Clemente A, Harrop A, McKercher S, Kaul M, Lipton SA: HIV/gp120 Decreases Adult Neural Progenitor Cell Proliferation via Checkpoint Kinase-Mediated Cell-Cycle Withdrawal and G1 Arrest. Cell Stem Cell 2007, 1:230-236.
• [14]Kaul M: HIV's double strike at the brain: neuronal toxicity and compromised neurogenesis. Front Biosci 2008, 13:2484-2494.
• [15]Jessberger S, Aigner S, Clemenson GD Jr, Toni N, Lie DC, Karalay O, Overall R, Kempermann G, Gage FH: Cdk5 regulates accurate maturation of newborn granule cells in the adult hippocampus. PLoS Biol 2008, 6:e272.
• [16]Lagace DC, Benavides DR, Kansy JW, Mapelli M, Greengard P, Bibb JA, Eisch AJ: Cdk5 is essential for adult hippocampal neurogenesis. Proc Natl Acad Sci USA 2008, 105:18567-18571.
• [17]Crews L, Patrick C, Adame A, Rockenstein E, Masliah E: Modulation of aberrant CDK5 signaling rescues impaired neurogenesis in models of Alzheimer's disease. Cell Death Dis 2011, 2:e120.
• [18]Sahlgren CM, Mikhailov A, Vaittinen S, Pallari HM, Kalimo H, Pant HC, Eriksson JE: Cdk5 regulates the organization of Nestin and its association with p35. Mol Cell Biol 2003, 23:5090-5106.
• [19]Matsubara M, Kusubata M, Ishiguro K, Uchida T, Titani K, Taniguchi H: Site-specific phosphorylation of synapsin I by mitogen-activated protein kinase and Cdk5 and its effects on physiological functions. J Biol Chem 1996, 271:21108-21113.
• [20]Soutar MP, Thornhill P, Cole AR, Sutherland C: Increased CRMP2 phosphorylation is observed in Alzheimer's disease; does this tell us anything about disease development? Curr Alzheimer Res 2009, 6:269-278.
• [21]Cole AR, Noble W, van Aalten L, Plattner F, Meimaridou R, Hogan D, Taylor M, LaFrancois J, Gunn-Moore F, Verkhratsky A, Oddo S, LaFerla F, Giese KP, Dineley KT, Duff K, Richardson JC, Yan SD, Hanger DP, Allan SM, Sutherland C: Collapsin response mediator protein-2 hyperphosphorylation is an early event in Alzheimer's disease progression. J Neurochem 2007, 103:1132-1144.
• [22]Yoshida H, Watanabe A, Ihara Y: Collapsin response mediator protein-2 is associated with neurofibrillary tangles in Alzheimer's disease. J Biol Chem 1998, 273:9761-9768.
• [23]Gelman BB, Nguyen TP: Synaptic proteins linked to HIV-1 infection and immunoproteasome induction: proteomic analysis of human synaptosomes. J Neuroimmune Pharmacol 2010, 5:92-102.
• [24]Zhou L, Diefenbach E, Crossett B, Tran SL, Ng T, Rizos H, Rua R, Wang B, Kapur A, Gandhi K, Brew BJ, Saksena NK: First evidence of overlaps between HIV-Associated Dementia (HAD) and non-viral neurodegenerative diseases: proteomic analysis of the frontal cortex from HIV+ patients with and without dementia. Mol Neurodegener 2010, 5:27. BioMed Central Full Text
• [25]Cole AR, Causeret F, Yadirgi G, Hastie CJ, McLauchlan H, McManus EJ, Hernandez F, Eickholt BJ, Nikolic M, Sutherland C: Distinct priming kinases contribute to differential regulation of collapsin response mediator proteins by glycogen synthase kinase-3 in vivo. J Biol Chem 2006, 281:16591-16598.
• [26]Uchida Y, Ohshima T, Yamashita N, Ogawara M, Sasaki Y, Nakamura F, Goshima Y: Semaphorin3A signaling mediated by Fyn-dependent tyrosine phosphorylation of collapsin response mediator protein 2 at tyrosine 32. J Biol Chem 2009, 284:27393-27401.
• [27]Goshima Y, Sasaki Y, Uchida Y, Yamashita M, Nakamura F: CRMP family protein: Novel targets for CDK5 that regulate axon guidance, synapse maturation, and cell migration. In Cyclin dependent kinase 5 (Cdk5). Edited by Ip NY, Tsai LH. New York: Springer; 2008:9-24.
• [28]Uchida Y, Ohshima T, Sasaki Y, Suzuki H, Yanai S, Yamashita N, Nakamura F, Takei K, Ihara Y, Mikoshiba K, Kolattukudy P, Honnorat J, Goshima Y: Semaphorin3A signalling is mediated via sequential Cdk5 and GSK3β phosphorylation of CRMP2: implication of common phosphorylating mechanism underlying axon guidance and Alzheimer's disease. Genes Cells 2005, 10:165-179.
• [29]Cole AR, Soutar MP, Rembutsu M, van Aalten L, Hastie CJ, McLauchlan H, Peggie M, Balastik M, Lu KP, Sutherland C: Relative resistance of Cdk5-phosphorylated CRMP2 to dephosphorylation. J Biol Chem 2008, 283:18227-18237.
• [30]Fukata Y, Itoh TJ, Kimura T, Menager C, Nishimura T, Shiromizu T, Watanabe H, Inagaki N, Iwamatsu A, Hotani H, Kaibuchi K: CRMP-2 binds to tubulin heterodimers to promote microtubule assembly. Nat Cell Biol 2002, 4:583-591.
• [31]Wang Y, White MG, Akay C, Chodroff RA, Robinson J, Lindl KA, Dichter MA, Qian Y, Mao Z, Kolson DL, Jordan-Sciutto KL: Activation of cyclin-dependent kinase 5 by calpains contributes to human immunodeficiency virus-induced neurotoxicity. J Neurochem 2007, 103:439-455.
• [32]Cruz JC, Tsai LH: A Jekyll and Hyde kinase: roles for Cdk5 in brain development and disease. Curr Opin Neurobiol 2004, 14:390-394.
• [33]Han P, Dou F, Li F, Zhang X, Zhang YW, Zheng H, Lipton SA, Xu H, Liao FF: Suppression of cyclin-dependent kinase 5 activation by amyloid precursor protein: a novel excitoprotective mechanism involving modulation of tau phosphorylation. J Neurosci 2005, 25:11542-11552.
• [34]Gu Y, Hamajima N, Ihara Y: Neurofibrillary tangle-associated collapsin response mediator protein-2 (CRMP-2) is highly phosphorylated on Thr-509, Ser-518, and Ser-522. Biochemistry 2000, 39:4267-4275.
• [35]Petratos S, Li QX, George AJ, Hou X, Kerr ML, Unabia SE, Hatzinisiriou I, Maksel D, Aguilar MI, Small DH: The β-amyloid protein of Alzheimer's disease increases neuronal CRMP-2 phosphorylation by a Rho-GTP mechanism. Brain 2008, 131:90-108.
• [36]Lee MH, Wang T, Jang MH, Steiner J, Haughey N, Ming GL, Song H, Nath A, Venkatesan A: Rescue of adult hippocampal neurogenesis in a mouse model of HIV neurologic disease. Neurobiol Dis 2011, 41:678-687.
• [37]Venkatesan A, Nath A, Ming GL, Song H: Adult hippocampal neurogenesis: regulation by HIV and drugs of abuse. Cell Mol Life Sci 2007, 64:2120-2132.
• [38]Charrier E, Reibel S, Rogemond V, Aguera M, Thomasset N, Honnorat J: Collapsin response mediator proteins (CRMPs): involvement in nervous system development and adult neurodegenerative disorders. Mol Neurobiol 2003, 28:51-64.
• [39]Rogemond V, Auger C, Giraudon P, Becchi M, Auvergnon N, Belin MF, Honnorat J, Moradi-Ameli M: Processing and nuclear localization of CRMP2 during brain development induce neurite outgrowth inhibition. J Biol Chem 2008, 283:14751-14761.
• [40]Goshima Y, Nakamura F, Strittmatter P, Strittmatter SM: Collapsin-induced growth cone collapse mediated by an intracellular protein related to UNC-33. Nature 1995, 376:509-514.
• [41]Wang LH, Strittmatter SM: Brain CRMP forms heterotetramers similar to liver dihydropyrimidinase. J Neurochem 1997, 69:2261-2269.
• [42]Cole AR, Knebel A, Morrice NA, Robertson LA, Irving AJ, Connolly CN, Sutherland C: GSK-3 phosphorylation of the Alzheimer epitope within collapsin response mediator proteins regulates axon elongation in primary neurons. J Biol Chem 2004, 279:50176-50180.
• [43]Arimura N, Inagaki N, Chihara K, Menager C, Nakamura N, Amano M, Iwamatsu A, Goshima Y, Kaibuchi K: Phosphorylation of collapsin response mediator protein-2 by Rho-kinase. Evidence for two separate signaling pathways for growth cone collapse. J Biol Chem 2000, 275:23973-23980.
• [44]Arimura N, Menager C, Fukata Y, Kaibuchi K: Role of CRMP-2 in neuronal polarity. J Neurobiol 2004, 58:34-47.
• [45]Sobue K, Agarwal-Mawal A, Li W, Sun W, Miura Y, Paudel HK: Interaction of neuronal Cdc2-like protein kinase with microtubule-associated protein tau. J Biol Chem 2000, 275:16673-16680.
• [46]Hou Z, Li Q, He L, Lim HY, Fu X, Cheung NS, Qi DX, Qi RZ: Microtubule association of the neuronal p35 activator of Cdk5. J Biol Chem 2007, 282:18666-18670.
• [47]Li G, Faibushevich A, Turunen BJ, Yoon SO, Georg G, Michaelis ML, Dobrowsky RT: Stabilization of the cyclin-dependent kinase 5 activator, p35, by paclitaxel decreases β-amyloid toxicity in cortical neurons. J Neurochem 2003, 84:347-362.
• [48]Gu Y, Ihara Y: Evidence that collapsin response mediator protein-2 is involved in the dynamics of microtubules. J Biol Chem 2000, 275:17917-17920.
• [49]Ray J, Gage FH: Differential properties of adult rat and mouse brain-derived neural stem/progenitor cells. Mol Cell Neurosci 2006, 31:560-573.
• [50]Desai A, Mitchison T: Fluorescence Procedures for the Actin and Tubulin Cytoskeleton in Fixed Cells. [http://mitchison.med.harvard.edu/protocols/gen1.html] webcite Accessed 8/25/2011.
• [51]Meijering E, Jacob M, Sarria JC, Steiner P, Hirling H, Unser M: Design and validation of a tool for neurite tracing and analysis in fluorescence microscopy images. Cytometry A 2004, 58:167-176.
• [52]Marongiu R, Spencer B, Crews L, Adame A, Patrick C, Trejo M, Dallapiccola B, Valente EM, Masliah E: Mutant Pink1 induces mitochondrial dysfunction in a neuronal cell model of Parkinson's disease by disturbing calcium flux. J Neurochem 2009, 108:1561-1574.
• [53]Rockenstein E, Mallory M, Mante M, Sisk A, Masliah E: Early formation of mature amyloid-b proteins deposits in a mutant APP transgenic model depends on levels of Ab1-42. J neurosci Res 2001, 66:573-582.
• [54]Achim CL, Heyes MP, Wiley CA: Quantitation of human immunodeficiency virus, immune activation factors, and quinolinic acid in AIDS brains. J Clin Invest 1993, 91:2769-2775.
• [55]Masliah E, Achim C, Ge N, DeTeresa R, Terry R, Wiley C: Spectrum of human immunodeficiency virus-associated neocortical damage. AnnNeurol 1992, 32:321-329.
• [56]Masliah E, Roberts ES, Langford D, Everall I, Crews L, Adame A, Rockenstein E, Fox HS: Patterns of gene dysregulation in the frontal cortex of patients with HIV encephalitis [Erratum appeared in J Neuroimmunol 2005, 162:197]. J Neuroimmunol 2004, 157:163-175.
• [57]Toggas S, Masliah E, Rockenstein E, Mucke L: Central nervous system damage produced by expression of the HIV-1 coat protein gp120 in transgenic mice. Nature 1994, 367:188-193.
• [58]D'Hooge R, Franck F, Mucke L, De Deyn PP: Age-related behavioural deficits in transgenic mice expressing the HIV-1 coat protein gp120. Eur J Neurosci 1999, 11:4398-4402.
• [59]Ohshima T, Ward JM, Huh CG, Longenecker G, Veeranna , Pant HC, Brady RO, Martin LJ, Kulkarni AB: Targeted disruption of the cyclin-dependent kinase 5 gene results in abnormal corticogenesis, neuronal pathology and perinatal death. Proc Natl Acad Sci USA 1996, 93:11173-11178.
• [60]Masliah E, Alford M, Adame A, Rockenstein E, Galasko D, Salmon D, Hansen LA, Thal LJ: Aβ1-42 promotes cholinergic sprouting in patients with AD and Lewy body variant of AD. Neurology 2003, 61:206-211.
• [61]Masliah E, Rockenstein E, Veinbergs I, Mallory M, Hashimoto M, Takeda A, Sagara , Sisk A, Mucke L: Dopaminergic loss and inclusion body formation in α-synuclein mice: Implications for neurodegenerative disorders. Science 2000, 287:1265-1269.