Pathogenic huntingtin inhibits fast axonal transport by activating JNK3 and phosphorylating kinesin
10.1038/nn.2346
Crossref journal-article
Springer Science and Business Media LLC
Nature Neuroscience (297)
Bibliography

Morfini, G. A., You, Y.-M., Pollema, S. L., Kaminska, A., Liu, K., Yoshioka, K., Björkblom, B., Coffey, E. T., Bagnato, C., Han, D., Huang, C.-F., Banker, G., Pigino, G., & Brady, S. T. (2009). Pathogenic huntingtin inhibits fast axonal transport by activating JNK3 and phosphorylating kinesin. Nature Neuroscience, 12(7), 864–871.

Authors 14
  1. Gerardo A Morfini (first)
  2. Yi-Mei You (additional)
  3. Sarah L Pollema (additional)
  4. Agnieszka Kaminska (additional)
  5. Katherine Liu (additional)
  6. Katsuji Yoshioka (additional)
  7. Benny Björkblom (additional)
  8. Eleanor T Coffey (additional)
  9. Carolina Bagnato (additional)
  10. David Han (additional)
  11. Chun-Fang Huang (additional)
  12. Gary Banker (additional)
  13. Gustavo Pigino (additional)
  14. Scott T Brady (additional)
References 50 Referenced 212
  1. Okun, M.S. Huntington's disease: what we learned from the original essay. Neurologist 9, 175–179 (2003). (10.1097/01.nrl.0000080952.78533.1f) / Neurologist by MS Okun (2003)
  2. Orr, H.T. & Zoghbi, H.Y. Trinucleotide repeat disorders. Annu. Rev. Neurosci. 30, 575–621 (2007). (10.1146/annurev.neuro.29.051605.113042) / Annu. Rev. Neurosci. by HT Orr (2007)
  3. Morfini, G., Pigino, G. & Brady, S.T. Polyglutamine expansion diseases: failing to deliver. Trends Mol. Med. 11, 64–70 (2005). (10.1016/j.molmed.2004.12.002) / Trends Mol. Med. by G Morfini (2005)
  4. Gunawardena, S. et al. Disruption of axonal transport by loss of huntingtin or expression of pathogenic polyQ proteins in Drosophila. Neuron 40, 25–40 (2003). (10.1016/S0896-6273(03)00594-4) / Neuron by S Gunawardena (2003)
  5. Lee, W.C., Yoshihara, M. & Littleton, J.T. Cytoplasmic aggregates trap polyglutamine-containing proteins and block axonal transport in a Drosophila model of Huntington's disease. Proc. Natl. Acad. Sci. USA 101, 3224–3229 (2004). (10.1073/pnas.0400243101) / Proc. Natl. Acad. Sci. USA by WC Lee (2004)
  6. Trushina, E. et al. Mutant huntingtin impairs axonal trafficking in mammalian neurons in vivo and in vitro. Mol. Cell. Biol. 24, 8195–8209 (2004). (10.1128/MCB.24.18.8195-8209.2004) / Mol. Cell. Biol. by E Trushina (2004)
  7. Morfini, G. et al. JNK mediates pathogenic effects of polyglutamine-expanded androgen receptor on fast axonal transport. Nat. Neurosci. 9, 907–916 (2006). (10.1038/nn1717) / Nat. Neurosci. by G Morfini (2006)
  8. Szebenyi, G. et al. Neuropathogenic forms of huntingtin and androgen receptor inhibit fast axonal transport. Neuron 40, 41–52 (2003). (10.1016/S0896-6273(03)00569-5) / Neuron by G Szebenyi (2003)
  9. Colin, E. et al. Huntingtin phosphorylation acts as a molecular switch for anterograde/retrograde transport in neurons. EMBO J. 27, 2124–2134 (2008). (10.1038/emboj.2008.133) / EMBO J. by E Colin (2008)
  10. Gauthier, L.R. et al. Huntingtin controls neurotrophic support and survival of neurons by enhancing BDNF vesicular transport along microtubules. Cell 118, 127–138 (2004). (10.1016/j.cell.2004.06.018) / Cell by LR Gauthier (2004)
  11. Engelender, S. et al. Huntingtin-associated protein 1 (HAP1) interacts with the p150Glued subunit of dynactin. Hum. Mol. Genet. 6, 2205–2212 (1997). (10.1093/hmg/6.13.2205) / Hum. Mol. Genet. by S Engelender (1997)
  12. Caviston, J.P., Ross, J.L., Antony, S.M., Tokito, M. & Holzbaur, E.L. Huntingtin facilitates dynein/dynactin-mediated vesicle transport. Proc. Natl. Acad. Sci. USA 104, 10045–10050 (2007). (10.1073/pnas.0610628104) / Proc. Natl. Acad. Sci. USA by JP Caviston (2007)
  13. DeBoer, S.R. et al. Conventional kinesin holoenzymes are composed of heavy and light chain homodimers. Biochemistry 47, 4535–4543 (2008). (10.1021/bi702445j) / Biochemistry by SR DeBoer (2008)
  14. Lazarov, O. et al. Axonal transport, amyloid precursor protein, kinesin-1 and the processing apparatus: revisited. J. Neurosci. 25, 2386–2395 (2005). (10.1523/JNEUROSCI.3089-04.2005) / J. Neurosci. by O Lazarov (2005)
  15. Wheeler, V.C. et al. Long glutamine tracts cause nuclear localization of a novel form of huntingtin in medium spiny striatal neurons in HdhQ92 and HdhQ111 knock-in mice. Hum. Mol. Genet. 9, 503–513 (2000). (10.1093/hmg/9.4.503) / Hum. Mol. Genet. by VC Wheeler (2000)
  16. Brill, L.B. II & Pfister, K.K. Biochemical and molecular analysis of the mammalian cytoplasmic dynein intermediate chain. Methods 22, 307–316 (2000). (10.1006/meth.2000.1083) / Methods by LB Brill II (2000)
  17. Brady, S.T., Pfister, K.K. & Bloom, G.S. A monoclonal antibody against kinesin inhibits both anterograde and retrograde fast axonal transport in squid axoplasm. Proc. Natl. Acad. Sci. USA 87, 1061–1065 (1990). (10.1073/pnas.87.3.1061) / Proc. Natl. Acad. Sci. USA by ST Brady (1990)
  18. Morfini, G., Szebenyi, G., Elluru, R., Ratner, N. & Brady, S.T. Glycogen synthase kinase 3 phosphorylates kinesin light chains and negatively regulates kinesin-based motility. EMBO J. 21, 281–293 (2002). (10.1093/emboj/21.3.281) / EMBO J. by G Morfini (2002)
  19. Donelan, M.J. et al. Ca2+-dependent dephosphorylation of kinesin heavy chain on beta-granules in pancreatic beta-cells. Implications for regulated beta-granule transport and insulin exocytosis. J. Biol. Chem. 277, 24232–24242 (2002). (10.1074/jbc.M203345200) / J. Biol. Chem. by MJ Donelan (2002)
  20. Apostol, B.L. et al. Mutant huntingtin alters MAPK signaling pathways in PC12 and striatal cells: ERK1/2 protects against mutant huntingtin-associated toxicity. Hum. Mol. Genet. 15, 273–285 (2006). (10.1093/hmg/ddi443) / Hum. Mol. Genet. by BL Apostol (2006)
  21. Merienne, K., Helmlinger, D., Perkin, G.R., Devys, D. & Trottier, Y. Polyglutamine expansion induces a protein-damaging stress connecting heat shock protein 70 to the JNK pathway. J. Biol. Chem. 278, 16957–16967 (2003). (10.1074/jbc.M212049200) / J. Biol. Chem. by K Merienne (2003)
  22. Liu, Y.F. Expression of polyglutamine-expanded Huntingtin activates the SEK1-JNK pathway and induces apoptosis in a hippocampal neuronal cell line. J. Biol. Chem. 273, 28873–28877 (1998). (10.1074/jbc.273.44.28873) / J. Biol. Chem. by YF Liu (1998)
  23. Coffey, E.T. et al. 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). (10.1523/JNEUROSCI.22-11-04335.2002) / J. Neurosci. by ET Coffey (2002)
  24. Fabian, M.A. et al. A small molecule-kinase interaction map for clinical kinase inhibitors. Nat. Biotechnol. 23, 329–336 (2005). (10.1038/nbt1068) / Nat. Biotechnol. by MA Fabian (2005)
  25. Barr, R.K., Kendrick, T.S. & Bogoyevitch, M.A. Identification of the critical features of a small peptide inhibitor of JNK activity. J. Biol. Chem. 277, 10987–10997 (2002). (10.1074/jbc.M107565200) / J. Biol. Chem. by RK Barr (2002)
  26. Dompierre, J.P. et al. Histone deacetylase 6 inhibition compensates for the transport deficit in Huntington's disease by increasing tubulin acetylation. J. Neurosci. 27, 3571–3583 (2007). (10.1523/JNEUROSCI.0037-07.2007) / J. Neurosci. by JP Dompierre (2007)
  27. Kozikowski, A.P. et al. Functional differences in epigenetic modulators-superiority of mercaptoacetamide-based histone deacetylase inhibitors relative to hydroxamates in cortical neuron neuroprotection studies. J. Med. Chem. 50, 3054–3061 (2007). (10.1021/jm070178x) / J. Med. Chem. by AP Kozikowski (2007)
  28. Gallo, K.A. & Johnson, G.L. Mixed-lineage kinase control of JNK and p38 MAPK pathways. Nat. Rev. Mol. Cell Biol. 3, 663–672 (2002). (10.1038/nrm906) / Nat. Rev. Mol. Cell Biol. by KA Gallo (2002)
  29. Qin, Z.H. et al. Huntingtin bodies sequester vesicle-associated proteins by a polyproline-dependent interaction. J. Neurosci. 24, 269–281 (2004). (10.1523/JNEUROSCI.1409-03.2004) / J. Neurosci. by ZH Qin (2004)
  30. Björkblom, B. et al. All JNKs can kill, but nuclear localization is critical for neuronal death. J. Biol. Chem. 283, 19704–19713 (2008). (10.1074/jbc.M707744200) / J. Biol. Chem. by B Björkblom (2008)
  31. Nishitoh, H. et al. ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats. Genes Dev. 16, 1345–1355 (2002). (10.1101/gad.992302) / Genes Dev. by H Nishitoh (2002)
  32. Coffey, E.T., Hongisto, V., Dickens, M., Davis, R.J. & Courtney, M.J. Dual roles for c-Jun N-terminal kinase in developmental and stress responses in cerebellar granule neurons. J. Neurosci. 20, 7602–7613 (2000). (10.1523/JNEUROSCI.20-20-07602.2000) / J. Neurosci. by ET Coffey (2000)
  33. Thomas, G.M., Lin, D.T., Nuriya, M. & Huganir, R.L. Rapid and bi-directional regulation of AMPA receptor phosphorylation and trafficking by JNK. EMBO J. 27, 361–372 (2008). (10.1038/sj.emboj.7601969) / EMBO J. by GM Thomas (2008)
  34. Ito, M. et al. Isoforms of JSAP1 scaffold protein generated through alternative splicing. Gene 255, 229–234 (2000). (10.1016/S0378-1119(00)00335-8) / Gene by M Ito (2000)
  35. Nühse, T.S., Stensballe, A., Jensen, O.N. & Peck, S.C. Large-scale analysis of in vivo phosphorylated membrane proteins by immobilized metal ion affinity chromatography and mass spectrometry. Mol. Cell. Proteomics 2, 1234–1243 (2003). (10.1074/mcp.T300006-MCP200) / Mol. Cell. Proteomics by TS Nühse (2003)
  36. Sack, S. et al. X-ray structure of motor and neck domains from rat brain kinesin. Biochemistry 36, 16155–16165 (1997). (10.1021/bi9722498) / Biochemistry by S Sack (1997)
  37. Jacobson, C., Schnapp, B. & Banker, G.A. A change in the selective translocation of the kinesin-1 motor domain marks the initial specification of the axon. Neuron 49, 797–804 (2006). (10.1016/j.neuron.2006.02.005) / Neuron by C Jacobson (2006)
  38. LaPointe, N.E. et al. The amino terminus of tau inhibits kinesin-dependent axonal transport: implications for filament toxicity. J. Neurosci. Res. 87, 440–451 (2009). (10.1002/jnr.21850) / J. Neurosci. Res. by NE LaPointe (2009)
  39. Pigino, G., Morfini, G., Mattson, M.P., Brady, S.T. & Busciglio, J. Alzheimer's presenilin 1 mutations impair kinesin-based axonal transport. J. Neurosci. 23, 4499–4508 (2003). (10.1523/JNEUROSCI.23-11-04499.2003) / J. Neurosci. by G Pigino (2003)
  40. Roy, S., Zhang, B., Lee, V.M. & Trojanowski, J.Q. Axonal transport defects: a common theme in neurodegenerative diseases. Acta Neuropathol. 109, 5–13 (2005). (10.1007/s00401-004-0952-x) / Acta Neuropathol. by S Roy (2005)
  41. McGuire, J.R., Rong, J., Li, S.H. & Li, X.J. Interaction of Huntingtin-associated protein-1 with kinesin light chain: implications in intracellular trafficking in neurons. J. Biol. Chem. 281, 3552–3559 (2006). (10.1074/jbc.M509806200) / J. Biol. Chem. by JR McGuire (2006)
  42. Li, H., Li, S.H., Yu, Z.X., Shelbourne, P. & Li, X.J. Huntingtin aggregate–associated axonal degeneration is an early pathological event in Huntington's disease mice. J. Neurosci. 21, 8473–8481 (2001). (10.1523/JNEUROSCI.21-21-08473.2001) / J. Neurosci. by H Li (2001)
  43. Carmichael, J., Sugars, K.L., Bao, Y.P. & Rubinsztein, D.C. Glycogen synthase kinase–3beta inhibitors prevent cellular polyglutamine toxicity caused by the Huntington's disease mutation. J. Biol. Chem. 277, 33791–33798 (2002). (10.1074/jbc.M204861200) / J. Biol. Chem. by J Carmichael (2002)
  44. Colin, E. et al. Akt is altered in an animal model of Huntington's disease and in patients. Eur. J. Neurosci. 21, 1478–1488 (2005). (10.1111/j.1460-9568.2005.03985.x) / Eur. J. Neurosci. by E Colin (2005)
  45. Garcia, M., Charvin, D. & Caboche, J. Expanded huntingtin activates the c-Jun terminal kinase/c-Jun pathway prior to aggregate formation in striatal neurons in culture. Neuroscience 127, 859–870 (2004). (10.1016/j.neuroscience.2004.05.054) / Neuroscience by M Garcia (2004)
  46. Gupta, S. et al. Selective interaction of JNK protein kinase isoforms with transcription factors. EMBO J. 15, 2760–2770 (1996). (10.1002/j.1460-2075.1996.tb00636.x) / EMBO J. by S Gupta (1996)
  47. Yang, D.D. et al. Absence of excitotoxicity-induced apoptosis in the hippocampus of mice lacking the Jnk3 gene. Nature 389, 865–870 (1997). (10.1038/39899) / Nature by DD Yang (1997)
  48. Bogoyevitch, M.A. & Kobe, B. Uses for JNK: the many and varied substrates of the c-Jun N-terminal kinases. Microbiol. Mol. Biol. Rev. 70, 1061–1095 (2006). (10.1128/MMBR.00025-06) / Microbiol. Mol. Biol. Rev. by MA Bogoyevitch (2006)
  49. Cha, J.H. Transcriptional signatures in Huntington's disease. Prog. Neurobiol. 83, 228–248 (2007). / Neurobiol. by JH Cha (2007)
  50. Han, D.K., Eng, J., Zhou, H. & Aebersold, R. Quantitative profiling of differentiation-induced microsomal proteins using isotope-coded affinity tags and mass spectrometry. Nat. Biotechnol. 19, 946–951 (2001). (10.1038/nbt1001-946) / Nat. Biotechnol. by DK Han (2001)
Dates
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Created 16 years, 2 months ago (June 14, 2009, 9:50 p.m.)
Deposited 2 years, 3 months ago (May 18, 2023, 8:03 p.m.)
Indexed 2 hours, 45 minutes ago (Sept. 3, 2025, 6:05 a.m.)
Issued 16 years, 2 months ago (June 14, 2009)
Published 16 years, 2 months ago (June 14, 2009)
Published Online 16 years, 2 months ago (June 14, 2009)
Published Print 16 years, 2 months ago (July 1, 2009)
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@article{Morfini_2009, title={Pathogenic huntingtin inhibits fast axonal transport by activating JNK3 and phosphorylating kinesin}, volume={12}, ISSN={1546-1726}, url={http://dx.doi.org/10.1038/nn.2346}, DOI={10.1038/nn.2346}, number={7}, journal={Nature Neuroscience}, publisher={Springer Science and Business Media LLC}, author={Morfini, Gerardo A and You, Yi-Mei and Pollema, Sarah L and Kaminska, Agnieszka and Liu, Katherine and Yoshioka, Katsuji and Björkblom, Benny and Coffey, Eleanor T and Bagnato, Carolina and Han, David and Huang, Chun-Fang and Banker, Gary and Pigino, Gustavo and Brady, Scott T}, year={2009}, month=jun, pages={864–871} }