Skip to main content
SpringerLink
Log in
Book cover

Hypoxia and Exercise pp 145–155Cite as

JNK Pathway as Therapeutic Target to Prevent Degeneration in the Central Nervous System

  • Conference paper

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 588))

Abstract

JNKs (c-Jun N-terminal kinases) are important transducing enzymes involved in many faces of cellular regulation such as gene expression, cell proliferation and programmed cell death. The activation of JNK pathway is critical for naturally occurring neuronal death during development as well as for pathological death of adult brain following different insults. In particular, JNKs play an important role in excitotoxicity and all related phenomena. Initial research concentrated on defining the components and organization of JNK signalling cascades, but more recent studies have begun to see JNK as the appropriate target for prevent cell loss. We used a specific JNK inhibitor, the cell permeable peptide D-JNKI1, to block JNK action in neuronal death following excitotoxicity in vitro and cerebral ischemia in vivo. Here we review our recent findings and we discuss the possibility of using D-JNKI1 as a therapeutic agent to prevent cell loss in the central nervous system.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   169.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Aarts M, Liu Y, Liu L, Besshoh S, Arundine M, Gurd JW, Wang YT, Salter MW, and Tymianski M. Treatment of ischemic brain damage by perturbing NMDA receptor-PSD-95 protein interactions. Science 298: 846–850, 2002.

    Article  PubMed  CAS  Google Scholar 

  2. Barr RK, Kendrick TS, and Bogoyevitch MA. Identification of the critical features of a small peptide inhibitor of JNK activity. JBiol Chem 277: 10987–10997, 2002.

    Article  CAS  Google Scholar 

  3. Behrens A, Sibilia M, and Wagner EF. Amino-terminal phosphorylation of c-Jun regulates stress-induced apoptosis and cellular proliferation. Nat Genet 21: 326–329, 1999.

    Article  PubMed  CAS  Google Scholar 

  4. Bennett BL, Sasaki DT, Murray BW, O’Leary EC, Sakata ST, Xu W, Leisten JC, Motiwala A, Pierce S, Satoh Y, Bhagwat SS, Manning AM, and Anderson DW. SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase. Proc Natl Acad Sci U S A 98: 13681–13686, 2001.

    Article  PubMed  CAS  Google Scholar 

  5. Bogoyevitch MA, Boehm I, Oakley A, Ketterman AJ, and Barr RK. Targeting the JNK MAPK cascade for inhibition: basic science and therapeutic potential. Biochim Biophys Acta 1697: 89–101, 2004.

    PubMed  CAS  Google Scholar 

  6. Bonny C, Oberson A, Negri S, Sauser C, and Schorderet DF. Cell-permeable peptide inhibitors of JNK: novel blockers of \-cell death. Diabetes 50: 77–82, 2001.

    Article  PubMed  CAS  Google Scholar 

  7. Borsello T and Bonny C. Use of cell-permeable peptides to prevent neuronal degeneration. Trends Mol Med 10: 239–244, 2004.

    Article  PubMed  CAS  Google Scholar 

  8. Borsello T, Clarke PG, Hirt L, Vercelli A, Repici M, Schorderet DF, Bogousslavsky J, and Bonny C. A peptide inhibitor of c-Jun N-terminal kinase protects against excitotoxicity and cerebral ischemia. Nat Med 9: 1180–1186, 2003.

    Article  PubMed  CAS  Google Scholar 

  9. Borsello T, Croquelois K, Hornung JP, and Clarke PG. N-methyl-d-aspartate-triggered neuronal death in organotypic hippocampal cultures is endocytic, autophagic and mediated by the c-Jun N-terminal kinase pathway. Eur J Neurosci 18: 473–485, 2003.

    Article  PubMed  Google Scholar 

  10. Bozyczko-Coyne D, Saporito MS, and Hudkins RL. Targeting the JNK pathway for therapeutic benefit in CNS disease. Curr Drug Target CNS Neurol Disord 1: 31–49, 2002.

    Article  CAS  Google Scholar 

  11. Brecht S, Kirchhof R, Chromik A, Willesen M, Nicolaus T, Raivich G, Wessig J, Waetzig V, Goetz M, Claussen M, Pearse D, Kuan CY, Vaudano E, Behrens A, Wagner E, Flavell RA, Davis RJ, and Herdegen T. Specific pathophysiological functions of JNK isoforms in the brain. Eur J Neurosci 21: 363–377, 2005.

    Article  PubMed  Google Scholar 

  12. Cavigelli M, Dolfi F, Claret FX, and Karin M. Induction of c-fos expression through JNK-mediated TCF/Elk-1 phosphorylation. Embo J 14: 5957–5964, 1995.

    PubMed  CAS  Google Scholar 

  13. Coffey ET, Hongisto V, Dickens M, Davis RJ, and Courtney MJ. Dual Roles for c-Jun N-Terminal Kinase in Developmental and Stress Responses in Cerebellar Granule Neurons. J Neurosci 20: 7602–7613, 2000.

    PubMed  CAS  Google Scholar 

  14. Coffey ET, Smiciene G, Hongisto V, Cao J, Brecht S, Herdegen T, and Courtney MJ. c-Jun N-terminal protein kinase (JNK) 2/3 is specifically activated by stress, mediating c-Jun activation, in the presence of constitutive JNK1 activity in cerebellar neurons. J Neurosci 22: 4335–4345, 2002.

    PubMed  CAS  Google Scholar 

  15. Del Villar K and Miller CA. Down-regulation of DENN/MADD, a TNF receptor binding protein, correlates with neuronal cell death in Alzheimer’s disease brain and hippocampal neurons. Proc Natl Acad Sci U S A 101:4210–4215, 2004.

    Article  PubMed  CAS  Google Scholar 

  16. Eynott PR, Nath P, Leung SY, Adcock IM, Bennett BL, and Chung KF. Allergen-induced inflammation and airway epithelial and smooth muscle cell proliferation: role of Jun N-terminal kinase. Br J Pharmacol 140: 1373–1380, 2003.

    Article  PubMed  CAS  Google Scholar 

  17. Glaser JR and Glaser EM. Neuron imaging with Neurolucida-a PC-based system for image combining microscopy. Comput Med Imaging Graph 14: 307–317, 1990.

    Article  PubMed  CAS  Google Scholar 

  18. Han Z, Boyle DL, Chang L, Bennett B, Karin M, Yang L, Manning AM, and Firestein GS. c-Jun N-terminal kinase is required for metal loproteinase expression and joint destruction in inflammatory arthritis. J Clin Invest 108: 73–81, 2001.

    Article  PubMed  CAS  Google Scholar 

  19. Herdegen T, Skene P, and Bahr M. The c-Jun transcription factor-bipotential mediator of neuronal death, survival and regeneration. Trends Neurosci 20: 227–231, 1997.

    Article  PubMed  CAS  Google Scholar 

  20. Inomata H, Nakamura Y, Hayakawa A, Takata H, Suzuki T, Miyazawa K, and Kitamura N. A scaffold protein JIP-lb enhances amyloid precursor protein phosphorylation by JNK and its association with kinesin light chain 1. J Biol Chem 278: 22946–22955, 2003.

    Article  PubMed  CAS  Google Scholar 

  21. Ip YT and Davis RJ. Signal transduction by the c-Jun N-terminal kinase (JNK)-from inflammation to development. Curr Opin Cell Biol 10: 205–219, 1998.

    Article  PubMed  CAS  Google Scholar 

  22. Kim HS, Park CH, Cha SH, Lee JH, Lee S, Kim Y, Rah JC, Jeong SJ, and Suh YH. Carboxyl-terminal fragment of Alzheimer’s APP destabilizes calcium homeostasis and renders neuronal cells vulnerable to excitotoxicity. Faseb J 14: 1508–1517, 2000.

    Article  PubMed  CAS  Google Scholar 

  23. Ko HW, Park KY, Kim H, Han PL, Kim YU, Gwag BJ, and Choi EJ. Ca2+-mediated activation of c-Jun N-terminal kinase and nuclear factor kappa B by NMDA in cortical cell cultures. J Neurochem 71: 1390–1395, 1998.

    Article  PubMed  CAS  Google Scholar 

  24. Kuan CY, Whitmarsh AJ, Yang DD, Liao G, Schloemer AJ, Dong C, Bao J, Banasiak KJ, Haddad GG, Flavell RA, Davis RJ, and Rakic P. A critical role of neural-specific JNK3 for ischemic apoptosis. Proc Natl Acad Sci USA 100: 15184–15189, 2003.

    Article  PubMed  CAS  Google Scholar 

  25. Marques CA, Keil U, Bonert A, Steiner B, Haass C, Muller WE, and Eckert A. Neurotoxic mechanisms caused by the Alzheimer’s disease-linked Swedish amyloid precursor protein mutation: oxidative stress, caspases, and the JNK pathway. J Biol Chem 278: 28294–28302, 2003.

    Article  PubMed  CAS  Google Scholar 

  26. Murakata C, Kaneko M, Gessner G, Angeles TS, Ator MA, O’Kane TM, McKenna BA, Thomas BA, Mathiasen JR, Saporito MS, Bozyczko-Coyne D, and Hudkins RL. Mixed lineage kinase activity of indolocarbazole analogues. Bioorg Med Chem Lett 12: 147–150, 2002.

    Article  PubMed  CAS  Google Scholar 

  27. Pulverer BJ, Kyriakis JM, Avruch J, Nikolakaki E, and Woodgett JR. Phosphorylation of c-jun mediated by MAP kinases. Nature 353: 670–674, 1991.

    Article  PubMed  CAS  Google Scholar 

  28. Putcha GV, Le S, Frank S, Besirli CG, Clark K, Chu B, Alix S, Youle RJ, LaMarche A, Maroney AC, and Johnson EM, Jr. JNK-mediated BIM phosphorylation potentiates BAX-dependent apoptosis. Neuron 38: 899–914, 2003.

    Article  PubMed  CAS  Google Scholar 

  29. Savinainen A, Garcia EP, Dorow D, Marshall J, and Liu YF. Kainate receptor activation induces mixed lineage kinase-mediated cellular signaling cascades via post-synaptic density protein 95. J Biol Chem 276: 11382–11386, 2001.

    Article  PubMed  CAS  Google Scholar 

  30. Schauwecker PE. Seizure-induced neuronal death is associated with induction of c-Jun N-terminal kinase and is dependent on genetic background. Brain Res 884: 116–128, 2000.

    Article  PubMed  CAS  Google Scholar 

  31. Schroeter H, Boyd CS, Ahmed R, Spencer JP, Duncan RF, Rice-Evans C, and Cadenas E. c-Jun N-terminal kinase (JNK)-mediated modulation of brain mitochondria function: new target proteins for JNK signalling in mitochondrion-dependent apoptosis. Biochem J 372: 359–369, 2003.

    Article  PubMed  CAS  Google Scholar 

  32. Schwarze SR, Ho A, Vocero-Akbani A, and Dowdy SF. In vivo protein transduction: delivery of a biologically active protein into the mouse. Science 285: 1569–1572, 1999.

    Article  PubMed  CAS  Google Scholar 

  33. Standen CL, Brownlees J, Grierson AJ, Kesavapany S, Lau KF, McLoughlin DM, and Miller CC. Phosphorylation of thr(668) in the cytoplasmic domain of the Alzheimer’s disease amyloid precursor protein by stress-activated protein kinase 1b (Jun N-terminal kinase-3). J Neurochem 76: 316–320, 2001.

    Article  PubMed  CAS  Google Scholar 

  34. Tezel G, Chauhan BC, LeBlanc RP, and Wax MB. Immunohistochemical assessment of the glial mitogen-activated protein kinase activation in glaucoma. Invest Ophthalmol Vis Sci 44: 3025–3033, 2003.

    PubMed  Google Scholar 

  35. Tournier C, Hess P, Yang DD, Xu J, Turner TK, Nimnual A, Bar-Sagi D, Jones SN, Flavell RA, and Davis RJ. Requirement of JNK for stress-induced activation of the cytochrome c-mediated death pathway. Science 288: 870–874, 2000.

    Article  PubMed  CAS  Google Scholar 

  36. Wang J, Van De Water TR, Bonny C, de Ribaupierre F, Puel JL, and Zine A. A peptide inhibitor of c-Jun N-terminal kinase protects against both aminoglycoside and acoustic trauma-induced auditory hair cell death and hearing loss. J Neurosci 23: 8596–8607, 2003.

    PubMed  CAS  Google Scholar 

  37. Wang LH, Besirli CG, and Johnson EM, Jr. Mixed-lineage kinases: a target for the prevention of neurodegeneration. Annu Rev Pharmacol Toxicol 44: 451–474, 2004.

    Article  PubMed  CAS  Google Scholar 

  38. Wang W, Shi L, Xie Y, Ma C, Li W, Su X, Huang S, Chen R, Zhu Z, Mao Z, Han Y, and Li M. SP600125, a new JNK inhibitor, protects dopaminergic neurons in the MPTP model of Parkinson’s disease. Neurosci Res 48: 195–202, 2004.

    Article  PubMed  CAS  Google Scholar 

  39. Yang DD, Kuan CY, Whitmarsh AJ, Rincon M, Zheng TS, Davis RJ, Rakic P, and Flavell RA. Absence of excitotoxicity-induced apoptosis in the hippocampus of mice lacking the Jnk3 gene. Nature 389: 865–870, 1997.

    Article  PubMed  CAS  Google Scholar 

  40. Yoshida H, Hastie CJ, McLauchlan H, Cohen P, and Goedert M. Phosphorylation of microtubule-associated protein tau by isoforms of c-Jun N-terminal kinase (JNK). J Neurochem 90: 352–358, 2004.

    Article  PubMed  CAS  Google Scholar 

  41. Zhang Y, Zhou L, and Miller CA. A splicing variant of a death domain protein that is regulated by a mitogen-activated kinase is a substrate for c-Jun N-terminal kinase in the human central nervous system. Proc Natl Acad Sci USA 95: 2586–2591, 1998.

    Article  PubMed  CAS  Google Scholar 

  42. Zhu X, Raina AK, Rottkamp CA, Aliev G, Perry G, Boux H, and Smith MA. Activation and redistribution of c-jun N-terminal kinase/stress activated protein kinase in degenerating neurons in Alzheimer’s disease. J Neurochem 76: 435–441, 2001.

    Article  PubMed  CAS  Google Scholar 

  43. Zipfel GJ, Babcock DJ, Lee JM, and Choi DW. Neuronal apoptosis after CNS injury: the roles of glutamate and calcium. J Neurotrauma 17: 857–869, 2000.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. University of Lausanne, Lausanne, Switzerland

    Mariaelena Repici & Tiziana Borsello

  2. Biol. Neurodeg. Disorders Lab, Istituto di ricerche Farmacologiche “Mario Negri”, Milano, Italy

    Tiziana Borsello

Authors
  1. Mariaelena Repici
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tiziana Borsello
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Altitude Research Center, University of Colorado Health Sciences Center, Mail Stop F524, PO Box 6508, Aurora, Colorado, 80045-0508

    Robert C. Roach Ph.D. (Research Director) (Research Director)

  2. UCSD Dept Medicine, 0623 9500 Gilman Avenue, La Jolla, CA, 92093-0623

    Peter D. Wagner

  3. Telluride Medical Center, 500 W. Pacific, Telluride, Colorado, 81435

    Peter H. Hackett

Rights and permissions

Reprints and permissions

Copyright information

© 2006 Springer Science+Business Media, LLC

About this paper

Cite this paper

Repici, M., Borsello, T. (2006). JNK Pathway as Therapeutic Target to Prevent Degeneration in the Central Nervous System. In: Roach, R.C., Wagner, P.D., Hackett, P.H. (eds) Hypoxia and Exercise. Advances in Experimental Medicine and Biology, vol 588. Springer, Boston, MA. https://doi.org/10.1007/978-0-387-34817-9_13

Download citation

Publish with us

Policies and ethics

Search

Navigation