Molecular Neurobiology

, Volume 43, Issue 3, pp 180–191 | Cite as

Collapsin Response Mediator Protein-2: An Emerging Pathologic Feature and Therapeutic Target for Neurodisease Indications

  • Kenneth Hensley
  • Kalina Venkova
  • Alexandar Christov
  • William Gunning
  • Joshua Park


Collapsin response mediator protein-2 (DPYSL2 or CRMP2) is a multifunctional adaptor protein within the central nervous system. In the developing brain or cell cultures, CRMP2 performs structural and regulatory functions related to cytoskeletal dynamics, vesicle trafficking and synaptic physiology whereas CRMP2 functions in adult brain are still being elucidated. CRMP2 has been associated with several neuropathologic or psychiatric conditions including Alzheimer’s disease (AD) and schizophrenia, either at the level of genetic polymorphisms; protein expression; post-translational modifications; or protein/protein interactions. In AD, CRMP2 is phosphorylated by glycogen synthase kinase-3β (GSK3β) and cyclin dependent protein kinase-5 (CDK5), the same kinases that act on tau protein in generating neurofibrillary tangles (NFTs). Phosphorylated CRMP2 collects in NFTs in association with the synaptic structure-regulating SRA1/WAVE1 (specifically Rac1-associated protein-1/WASP family verprolin-homologous protein-1) complex. This phenomenon could plausibly contribute to deficits in neural and synaptic structure that have been well documented in AD. This review discusses the essential biology of CRMP2 in the context of nascent data implicating CRMP2 perturbations as either a correlate of, or plausible contributor to, diverse neuropathologies. A discussion is made of recent findings that the atypical antidepressant tianeptine increases CRMP2 expression, whereas other, neuroactive small molecules including the epilepsy drug lacosamide and the natural brain metabolite lanthionine ketimine appear to bind CRMP2 directly with concomitant affects on neural structure. These findings constitute proofs-of-concept that pharmacological manipulation of CRMP2 is possible and hence, may offer new opportunities for therapy development against certain neurological diseases.


CRMP2 Alzheimer Schizophrenia Epilepsy Lanthionine Tianeptine Lacosamide 



This work was partially supported by a grant from the Judith and Jean Pape Adams Charitable Foundation (JJPAF). The authors thank Drs. Joseph Margiotta and Marthe Howard of the University of Toledo Medical Center for advice and guidance regarding DRG culture techniques. We thank Paula Kramer of the University of Toledo Medical Center for technical assistance in performing immunohistochemistry of AD brain specimens. We thank Professor Kozo Kaibuchi of the Nagoya University Graduate School of Medicine for his generous gift of antibodies against CRMP2 phospho-epitopes.


KH is an inventor on an issued US Patent no. 7,683,055 related to composition and use of lanthionine derivatives for treatment of inflammatory diseases.


  1. 1.
    Goshima Y, Nakamura F, Strittmatter P, Strittmatter SM (1995) Collapsin-induced growth cone collapse mediated by an intracellular protein related to UNC-33. Nature 376:509–514PubMedCrossRefGoogle Scholar
  2. 2.
    Inagaki N, Chihara K, Arimura N, Menager C, Kawano Y, Matsuo N, Nishimura T, Amano M, Kaibuchi K (2001) CRMP-2 induces axons in cultured hippocampal neurons. Nat Neurosci 4:781–782PubMedCrossRefGoogle Scholar
  3. 3.
    Cole AR, Knebel A, Morrice NA, Robertson LA, Irving AJ, Connolly CN, Sutherland C (2004) GSK-3 phosphorylation of the Alzheimer epitope within collapsing response mediator proteins regulates axon elongation in primary neurons. J Biol Chem 279:50176–40180PubMedCrossRefGoogle Scholar
  4. 4.
    Yoshimura T, Kawano Y, Arimura N, Kawabata S, Kikuchi A, Kaibuchi K (2005) GSK-3β regulates phosphorylation of CRMP-2 and neuronal polarity. Cell 120:137–149PubMedCrossRefGoogle Scholar
  5. 5.
    Deo RC, Schmidt EF, Elhabazi A, Togashi H, Burley SK, Strittmatter SM (2004) Structural bases for CRMP function in plexin-dependent semaphoring 3A signaling. EMBO J 23:9–22PubMedCrossRefGoogle Scholar
  6. 6.
    Charrier E, Riebel S, Rogemond V, Aguera M, Thomasset N, Honnorat J (2003) Collapsin response mediator proteins (CRMPs): involvement in nervous system development and adult neurodegenerative disorders. Mol Neurobiol 203:51–63CrossRefGoogle Scholar
  7. 7.
    Quach TT, Duchemin A-M, Rogemond V, Aguera M, Honnorat J, Belin M-F, Kolattukudy PE (2004) Involvement of collapsing response mediator proteins in the neurite extension induced by neurotrophins in dorsal root ganglion neurons. Mol Cell Neurosci 25:433–443PubMedCrossRefGoogle Scholar
  8. 8.
    Arimura N, Inagaki N, Chihara K, Menager C, Nakamura N, Iwamatsu A (2000) Phosphorylation of CRMP-2 by Rho kinase: evidence for two separate signaling pathways for growth cone collapse. J Biol Chem 275:23,973–23,980CrossRefGoogle Scholar
  9. 9.
    Arimura N, Meneger C, Fukata Y, Kaibuchi K (2004) Role of CRMP-2 in neuronal polarity. J Neurobiol 58:34–47PubMedCrossRefGoogle Scholar
  10. 10.
    Kawano Y, Yoshimura T, Tsuboi D, Kawabata S, Kaneko-Kawano T, Shirataki H, Takenawa T, Kaibuchi K (2005) CRMP-2 is involved in kinesin-1-dependent transport of the Swa-1/WAVE1 complex and axon formation. Mol Cell Biol 25:9920–9935PubMedCrossRefGoogle Scholar
  11. 11.
    Patrakitkomjorn S, Kobayashi D, Morikawa T, Wilson MM, Tsubota N, Irie A, Ozawa T, Aoki M, Arimura N, Kaibuchi K, Sava H, Araki N (2008) Neurofibromatosis type 1 (NF1) tumor suppressor, neurofibromin, regulates the neuronal differentiation of PC12 cells via its associated protein, CRMP-2. J Biol Chem 283:9399–9414PubMedCrossRefGoogle Scholar
  12. 12.
    Brittain JM, Piekarz AD, Wang Y, Kondo T, Cummins TR, Khanna R (2009) An atypical role for collapsing response mediator protein 2 (CRMP-2) in neurotransmitter release via interaction with presynaptic voltage-gated calcium channels. J Biol Chem 284:31375–31390PubMedCrossRefGoogle Scholar
  13. 13.
    Hensley K, Christov A, Kamat S, Zhang XC, Jackson KW, Snow S, Post J (2010) Proteomic identification of binding partners for the brain metabolite lanthionine ketimine (LK) and documentation of LK effects on microglia and motoneuron cell cultures. J Neurosci 30:2979–2988PubMedCrossRefGoogle Scholar
  14. 14.
    Chu CC, Wang JJ, Chen KT, Shieh JP, Wang LK, Shui HA, Ho ST (2010) Neurotrophic effects of tianeptine on hippocampal neurons: a proteomic approach. J Proteome Res 9:936–944PubMedCrossRefGoogle Scholar
  15. 15.
    Rogemond V, Auger C, Giraudon P, Bechi M, Auvergnon N, Belin M-F, Honnorat J, Moradi-Ameli M (2008) Processing and nuclear localization of CRMP2 during brain development induce neurite outgrowth inhibition. J Biol Chem 283:14751–14761PubMedCrossRefGoogle Scholar
  16. 16.
    Majava V, Loytynoja N, Chen W-Q, Lubec G, Kursula P (2008) Crystal and solution structure, stability, and post-translational modifications of collapsing response mediator protein-2. FEBS J 275:4583–4596PubMedCrossRefGoogle Scholar
  17. 17.
    Zhu JX, Doyle HA, Mamula MJ, Aswad DW (2006) Protein repair in the brain, proteomic analysis of endogenous substrates for protein l-isoaspartyl methyltransferase in mouse brain. J Biol Chem 281:33802–33813PubMedCrossRefGoogle Scholar
  18. 18.
    Cole RN, Hart GW (2001) Cytosolic O-glycosylation is abundant in nerve terminals. J Neurochem 79:1080–1089PubMedCrossRefGoogle Scholar
  19. 19.
    Owen JB, Di Domenico F, Sultana R, Perluigi M, Cini C, Pierce WM, Butterfield DA (2009) Proteomics-determined differences in the concanavalin-a-fractionated proteome of hippocampus and inferior parietal lobule in subjects with Alzheimer's disease and mild cognitive impairment: implications for progression of AD. J Proteome Res 8:471–482PubMedCrossRefGoogle Scholar
  20. 20.
    Reed TT, Pierce WM, Markesbery WR, Butterfield DA (2009) Proteomic identification of HNE-bound proteins in early Alzheimer disease: insights into the role of lipid peroxidation in the progression of AD. Br Res 1274:66–76CrossRefGoogle Scholar
  21. 21.
    Chae YC, Lee S, Heo K, Ha SH, Jung Y, Kim JH, Ihara Y, Suh PG, Ryu SH (2009) Collapsin response mediator protein-2 regulates neurite formation by modulating tubulin GTPase activity. Cell Signal 21:1818–1826PubMedCrossRefGoogle Scholar
  22. 22.
    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 (2005) Semaphorin3A Signaling is mediated via sequential Cdk5 and GSK3beta phosphorylation of CRMP2: implication of common phosphorylating mechanism underlying axon guidance and Alzheimer's disease. Genes Cells 10:165–179PubMedCrossRefGoogle Scholar
  23. 23.
    Soutar MP, Thornhill P, Cole AR, Sutherland C (2009) Increased CRMP2 phosphorylation is observed in Alzheimer’s disease: does this tell us anything about disease development? Curr Alz Res 6:269–278CrossRefGoogle Scholar
  24. 24.
    Li T, Hawkes C, Qureshi HY, Kar S, Paudel HK (2006) Cyclin-dependent protein kinase 5 primes microtubule-associated protein Tau site-specifically for glycogen synthase kinase 3beta. Biochemistry 14:3134–3145CrossRefGoogle Scholar
  25. 25.
    Lykissas MG, Batistatou AK, Konstantinos A, Charalabopoulos KA, Beris AE (2007) The role of neurotrophins in axon guidance, growth and regeneration. Curr Neurovas Res 4:143–151CrossRefGoogle Scholar
  26. 26.
    Arimura N, Kimura T, Nakamuta S, Taya S, Funahashi Y, Hattori A, Shimada A, Menager C, Kawabata S, Jujii K, Iwamatsu A, Segal RA, Fukuda M, Kaibuchi K (2009) Anterograde transport of TrkB in axons is mediated by direct interaction with Slp1 and Rab27. Dev Cell 15:675–686CrossRefGoogle Scholar
  27. 27.
    Pollitt A, Insall RH (2009) WASP and SCAR/WAVE proteins: the drivers of actin assembly. J Cell Sci 122:2575–2578PubMedCrossRefGoogle Scholar
  28. 28.
    Nishimura T, Fukata Y, Kato K, Yamaguchi T, Matsuura Y, Kamiguchi H, Kaibuchi K (2003) CRMP-2 regulates polarized numb-mediated endocytosis for axon growth. Nat Cell Biol 5:819–826PubMedCrossRefGoogle Scholar
  29. 29.
    Rahajeng J, Giridharan SS, Naslavsky N, Caplan S (2010) Collapsin response mediator protein-2 (CRMP2) regulates trafficking by linking endocytic regulatory proteins to dynein motors. J Biol Chem 285:31918–31922PubMedCrossRefGoogle Scholar
  30. 30.
    Price DL, Thinakaran G, Borchelt DR, et al. (1998) Neuropathology of Alzheimer's disease and animal models, in The neuropathology of dementing disorders, Markesbery, WR, ed., Edward Arnold, London, UK, pp. 121-141Google Scholar
  31. 31.
    Hanks SD, Flood DG (1991) Region-specific stability of dendritic extent in normal human aging and regression in Alzheimer’s disease. I. CA1 of hippocampus. Br Res 54:63–82CrossRefGoogle Scholar
  32. 32.
    Scott SA (1993) Dendritic atrophy and remodeling of amygdaloid neurons in Alzheimer’s disease. Dementia 4:264–271PubMedGoogle Scholar
  33. 33.
    Duyckaerts C, Delatour B, Potier M-C (2009) Classification and basic pathology of Alzheimer’s disease. Acta Neuropathol 118:5–36PubMedCrossRefGoogle Scholar
  34. 34.
    Arendt T (2009) Synaptic degeneration in Alzheimer’s disease. Acta Neuropathol 118:167–179PubMedCrossRefGoogle Scholar
  35. 35.
    Scheff SW, Price DA, Schmitt FA, DeKosky ST, Mufson EJ (2007) Hippocampal synaptic loss in early Alzheimer’s disease and mild cognitive impairment. Neurology 68:1501–1508PubMedCrossRefGoogle Scholar
  36. 36.
    Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayad R, Metherate R, Mattson MP, Akbari Y, LaFerla FM (2003) Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Aβ and synaptic dysfunction. Nature 39:409–421Google Scholar
  37. 37.
    Yoshida H, Watanabe A, Ihara Y (1998) Collapsin response mediator protein-2 is associated with neurofibrillary tangles in Alzheimer’s disease. J Biol Chem 273:9761–9768PubMedCrossRefGoogle Scholar
  38. 38.
    Cole AR, Noble W, van Aalten L, Plattner F, Meimaridou R, Hogan D, Taylor M, LaFrancois J, Gunn-Moore F, Verkhratski A, Oddo S, LaFerla F, Giese KP, Dineley KT, Duff K, Richardson JC, Yan SD, Hanger DP, Allan SM, Sutherland C (2007) Collapsin response mediator protein-2 hyperphosphorylation is an early event in Alzheimer’s disease progression. J Neurochem 103:1132–1144PubMedCrossRefGoogle Scholar
  39. 39.
    Gu Y, Hamajima N, Ihara Y (2000) Tangle-associated collapsin response mediator protein-2 (CRMP-2) is highly phosphorylated on Thr-509, Ser-518, Ser-522. Biochemistry 39:4267–4275PubMedCrossRefGoogle Scholar
  40. 40.
    Wang Q, Woltier RL, Cimino PJ, Pan C, Montine KS, Zhang J, Montine TF (2005) Proteomic analysis of neurofibrillary tangles in Alzheimer disease identifies GAPDH as a detergent-insoluble paired helical filament Tau binding protein. FASEB J 19:869–871PubMedCrossRefGoogle Scholar
  41. 41.
    Takata K, Kitamura Y, Nakata Y, Matsuoka Y, Taomimoto H, Taniguchi T, Shimohama S (2009) Involvement of WAVE accumulation in Aβ/APP pathology-dependent tangle modification in Alzheimer’s disease. Am J Pathol 175:17–24PubMedCrossRefGoogle Scholar
  42. 42.
    Kamat CD, Gadal S, Mhatre MC, Williamson KS, Pye QN, Hensley K (2009) Antioxidants in central nervous system diseases: preclinical promise and translational challenges. J Alzheimer’s Dis 15:473–493Google Scholar
  43. 43.
    Martinez A, Portero-Otin M, Pamplona R, Ferrer I (2010) Protein targets of oxidative damage in human neurodegenerative diseases with abnormal protein aggregates. Brain Pathol 20:281–297PubMedCrossRefGoogle Scholar
  44. 44.
    Pawlik M, Otero DA, Park M, Fischer WH, Levy E, Saitoh T (2007) Proteins that bind to the RERMS region of beta amyloid precursor protein. Biochem Biophys Res Commun 355:907–912PubMedCrossRefGoogle Scholar
  45. 45.
    Nakata K, Ujike H, Sakai A, Takaki M, Imamura T, Tanaka Y, Kuroda S (2003) The human dihydropyrimidinase-related protein 2 gene on chromosome 8p21 is associated with paranoid-type schizophrenia. Biol Psychiatry 53:571–576PubMedCrossRefGoogle Scholar
  46. 46.
    Koide T, Aleksic B, Ito Y, Usui H, Yoshima A, Inada T, Suzuki M, Hashimoto R, Takeda M, Iwata N, Ozaki N (2010) A Two-stage case-control association study of the dihydropyrimidinase-like 2 gene (DPYSL2) with schizophrenia in Japanese subjects. J Hum Genet 55:469–472PubMedCrossRefGoogle Scholar
  47. 47.
    Fallin MD, Lasseter VK, Avramopoulos D, Nicodemus KK, Wolyniec PS, McGrath JA, Steel G, Nestadt G, Liang KY, Huganir RL, Valle D, Pulver AE (2005) Bipolar I disorder and schizophrenia: a 440-single-nucleotide polymorphism screen of 64 candidate genes among Ashkenazi Jewish case-parent trios. Am J Hum Genet 77:918–936PubMedCrossRefGoogle Scholar
  48. 48.
    Martins de Souza D, Dias-Neto E, Schmitt A, Falkai P, Gormanns P, MacCarrone G, Turck CW, Gattaz WF (2010) Proteome analysis of schizophrenia brain tissue. World J Biol Psychiatry 11:110–120PubMedCrossRefGoogle Scholar
  49. 49.
    Johnston-Wilson NL, Sims CD, Hofmann JP, Anderson L, Shore AD, Torrey EF, Yolken RH (2000) Disease-specific alterations in frontal cortex brain proteins in schizophrenia, biopolar disorder, and major depressive disorder. Mol Psychiatry 5:142–149PubMedCrossRefGoogle Scholar
  50. 50.
    Arai M, Itokawa M (2010) A hard road in psychiatric genetics: schizophrenia and DPYSL2. J Hum Genet 55:397–399PubMedCrossRefGoogle Scholar
  51. 51.
    Bergson C, Levenson R, Goldman-Rakic PS, Lidow MS (2003) Dopanine receptor-interacting proteins: the Ca2+ connection in dopamine signaling. Trends Pharmacol Sci 24:486–492PubMedCrossRefGoogle Scholar
  52. 52.
    Bojarski L, Debowska K, Wojda U (2010) In vitro findings of alterations in intracellular calcium homeostasis in schizophrenia. Prog Neuro psychopharmacol Biol 34:1367–1374CrossRefGoogle Scholar
  53. 53.
    Kodama Y, Murakumo Y, Ichihara M, Kawai K, Shimono Y, Takahashi M (2004) Induction of CRMP-2 by GDNF and analysis of the CRMP-2 promoter region. Biochem Biophys Res Commun 320:108–115PubMedCrossRefGoogle Scholar
  54. 54.
    Demotes-Mainard F, Galley P, Manciet G, Vinson G, Salvadori C (1998) Pharmacokinetics of the antidepressant tianeptine at steady state in the elderly. J Clin Pharmacol 31:174–178Google Scholar
  55. 55.
    Preskorn SH (2004) Tianeptine: a facilitator of the reuptake of serotonin and norepinephrine as an antidepressant? J Psychiatr Pract 20:323–330CrossRefGoogle Scholar
  56. 56.
    Kasper S, Olie JP (2002) A meta-analysis of randomized controlled trials of tianeptine versus SSRI in the short-term treatment of depression. Eur Psychiatry 17(Suppl 3):331–340PubMedCrossRefGoogle Scholar
  57. 57.
    Sobow TM, Maczkiewicz M, Kloszewska I (2001) Tianeptine versus fluoxetin in the treatment of depression complicating Alzheimer’s disease. Int J Geriatr Psychiatry 16:1108–1109PubMedCrossRefGoogle Scholar
  58. 58.
    Jaffard R, Mocaer E, Poignant JC, Micheau J, Marighetto A, Meunier M, Beracochea D (1991) Effects of tianeptine on spontaneous alternation, simple and concurrent spatial discrimination learning and on alcohol-induced alternation deficits in mice. Behav Pharmacol 1:37–46Google Scholar
  59. 59.
    Magarinos AM, Deslandes A, McEwen BS (1999) Effects of antidepressants and benzodiazepine treatments on the dendritic structure of CA2 pyramidal neurons after chronic stress. Eur J Pharmacol 371:113–122PubMedCrossRefGoogle Scholar
  60. 60.
    Kelemen A, Halász P (2010) Lacosamide for the prevention of partial onset seizures in epileptic adults. Neuropsychiatr Dis Treat 2010:465–471CrossRefGoogle Scholar
  61. 61.
    Beyreuther B, Freitag J, Heers C, Krebsfanger N, Scharfenecker U, Stohr T (2007) Lacosamide: a review of preclinical properties. CNS Drug Rev 13:21–42PubMedCrossRefGoogle Scholar
  62. 62.
    Bee LA, Dickenson AH (2009) Effects of lacosamide, a novel sodium channel modulator, on dorsal horn neuronal responses in a rat model of neuropathy. Neuropharm 57:472–479CrossRefGoogle Scholar
  63. 63.
    Higgins GA, Brevsse N, Undzys E, Kuo C, Joharchi N, Derksen DR, Xin T, Isaac M, Slassi M (2009) The anti-epileptic drug lacosamide (vimpat) has anxiolytic property in rodents. Eur J Pharmacol 624:1–9PubMedCrossRefGoogle Scholar
  64. 64.
    Cavallini D, Ricci G, Dupre S, Pecci L, Costa M, Matarese RM, Pensa B, Antonuci A, Solinas SP, Fontana M (1991) Sulfur-containing cyclic ketimines and imino acids a novel family of endogenous products in search for a role. Eur J Biochem 202:217–223PubMedCrossRefGoogle Scholar
  65. 65.
    Cooper AJ, Anders MW (1990) Glutamine transaminase K and cysteine conjugate-lyase. Ann NY Acad Sci 585:118–127PubMedCrossRefGoogle Scholar
  66. 66.
    Cooper AJL (2004) The role of glutamine transaminase K (GTK) in sulfur and alpha-keto acid metabolism in the brain, and in the possible bioactivation of neurotoxicants. Neurochem Int 44:557–577PubMedCrossRefGoogle Scholar
  67. 67.
    Hensley K, Venkova K, Christov A (2010) Emerging biological importance of central nervous system lanthionines. Molecules 15:5581–5594PubMedCrossRefGoogle Scholar
  68. 68.
    Hensley, K. Lanthionine-related compounds for the treatment of inflammatory diseases. US Patent No. 7,683,055. Issued 3/23/2010Google Scholar
  69. 69.
    Ricci G, Vesci L, nardini M, Arduini A, Storto S, Rosato N, Cavallini D (1989) Detection of 2H–1, 4-thiazine-5, 6-dihydro-3, 5-dicarboxylic acid (lanthionine ketimine) in the bovine brain by a fluorometric assay. Biochim Biophys Acta 990:211–215PubMedGoogle Scholar
  70. 70.
    Chritin M, Savasta M, Besson G (2006) Benefit of tianeptine and morphine in a transgenic model of familial amyotrophic lateral sclerosis. Amyotroph Lateral Scler 7:32–37PubMedCrossRefGoogle Scholar
  71. 71.
    Zhang Z, Majava V, Greffier A, Hayes RL, Kursula P, Wang KK (2009) Collapsin response mediator protein-2 is a calmodulin-binding protein. Cell Mol Life Sci 66:526–536PubMedCrossRefGoogle Scholar
  72. 72.
    Neuron. In: Wikipedia, the free encyclopedia. Available at:
  73. 73.
    Margiotta JF, Howard MJ (1994) Eye extract factors promote the expression of acetylcholine sensitivity in chick dorsal root ganglion neurons. Dev Biol 163:188–201PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Kenneth Hensley
    • 1
    • 2
  • Kalina Venkova
    • 1
  • Alexandar Christov
    • 1
  • William Gunning
    • 1
  • Joshua Park
    • 2
  1. 1.Department of Pathology, MS 1090University of Toledo Health Science CenterToledoUSA
  2. 2.Department of Neurosciences, MS 1090University of Toledo Health Science CenterToledoUSA

Personalised recommendations