Preferential accumulation of N-terminal mutant huntingtin in the nuclei of striatal neurons is regulated by phosphorylation

Human Molecular Genetics

Volumn 20, Issue 7, 2011, Pages 1424-1437

  Havel, Lauren S ^a   Wang, Chuan En ^a   Wade, Brandy ^a   Huang, Brenda ^a   Li, Shihua ^a   Li, Xiao Jiang ^a  

^a EMORY UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

HUNTINGTIN; NUCLEOPORIN; PROTEIN TRP; SERINE; UNCLASSIFIED DRUG;

AMINO TERMINAL SEQUENCE; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL TISSUE; ARTICLE; BRAIN NERVE CELL; BRAIN NUCLEUS; FEMALE; MALE; MOUSE; MUTANT; NONHUMAN; PRIORITY JOURNAL; PROTEIN AGGREGATION; PROTEIN BINDING; PROTEIN PHOSPHORYLATION; RAT; STRIATE CORTEX;

ANIMALS; CORPUS STRIATUM; HEK293 CELLS; HUMANS; HUNTINGTON DISEASE; MICE; MICE, MUTANT STRAINS; MUTATION; NERVE TISSUE PROTEINS; NEURONS; NUCLEAR PORE; NUCLEAR PROTEINS; PHOSPHORYLATION; POLYGLUTAMIC ACID; PROTEIN STRUCTURE, TERTIARY;

MUS;

EID: 79952615363     PISSN: 09646906     EISSN: 14602083     Source Type: Journal    
DOI: 10.1093/hmg/ddr023     Document Type: Article

References (50)

1. DiFiglia, M., Sapp, E., Chase, K.O., Davies, S.W., Bates, G.P., Vonsattel, J.P. and Aronin, N. (1997) Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science, 277, 1990-1993.
2. Gutekunst, C.A., Li, S.H., Yi, H., Mulroy, J.S., Kuemmerle, S., Jones, R., Rye, D., Ferrante, R.J., Hersch, S.M. and Li, X.J. (1999) Nuclear and neuropil aggregates in Huntington's disease: relationship to neuropathology. J. Neurosci., 19, 2522-2534.
3. Orr, H.T. and Zoghbi, H.Y. (2007) Trinucleotide repeat disorders. Annu. Rev. Neurosci., 30, 575-621.
4. Van Raamsdonk, J.M., Murphy, Z., Slow, E.J., Leavitt, B.R. and Hayden, M.R. (2005) Selective degeneration and nuclear localization of mutant huntingtin in the YAC128 mouse model of Huntington disease. Hum. Mol. Genet., 14, 3823-3835.
5. Landles, C. and Bates, G.P. (2004) Huntingtin and the molecular pathogenesis of Huntington's disease. Fourth in molecular medicine review series. EMBO Rep., 5, 958-963.
6. Sadri-Vakili, G. and Cha, J.H. (2006) Mechanisms of disease: histone modifications in Huntington's disease. Nat. Clin. Pract. Neurol., 2, 330-338.
7. Havel, L.S., Li, S. and Li, X.J. (2009) Nuclear accumulation of polyglutamine disease proteins and neuropathology. Mol. Brain, 2, 21.
8. Wheeler, V.C., White, J.K., Gutekunst, C.A., Vrbanac, V., Weaver, M., Li, X.J., Li, S.H., Yi, H., Vonsattel, J.P., Gusella, J.F. et al. (2000) 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.
9. Li, H., Li, S.H., Johnston, H., Shelbourne, P.F. and Li, X.J. (2000) Amino-terminal fragments of mutant huntingtin show selective accumulation in striatal neurons and synaptic toxicity. Nat. Genet., 25, 385-389.
10. Lin, C.H., Tallaksen-Greene, S., Chien, W.M., Cearley, J.A., Jackson, W.S., Crouse, A.B., Ren, S., Li, X.J., Albin, R.L. and Detloff, P.J. (2001) Neurological abnormalities in a knock-in mouse model of Huntington's disease. Hum. Mol. Genet., 10, 137-144.
11. Gusella, J.F., MacDonald, M.E., Ambrose, C.M. and Duyao, M.P. (1993) Molecular genetics of Huntington's disease. Arch. Neurol., 50, 1157-1163.
12. Vonsattel, J.P. and DiFiglia, M. (1998) Huntington disease. J. Neuropathol. Exp. Neurol., 57, 369-384.
13. Menalled, L.B. and Chesselet, M.F. (2002) Mouse models of Huntington's disease. Trends Pharmacol. Sci., 23, 32-39.
14. Heng, M.Y., Detloff, P.J. and Albin, R.L. (2008) Rodent genetic models of Huntington disease. Neurobiol. Dis., 32, 1-9.
15. Wellington, C.L., Leavitt, B.R. and Hayden, M.R. (2000) Huntington disease: new insights on the role of huntingtin cleavage. J. Neural. Transm. Suppl., 58, 1-17.
16. Imarisio, S., Carmichael, J., Korolchuk, V., Chen, C.W., Saiki, S., Rose, C., Krishna, G., Davies, J.E., Ttofi, E., Underwood, B.R. et al. (2008) Huntington's disease: from pathology and genetics to potential therapies. Biochem. J., 412, 191-209.
17. Miller, J.P., Holcomb, J., Al-Ramahi, I., de Haro, M., Gafni, J., Zhang, N., Kim, E., Sanhueza, M., Torcassi, C., Kwak, S. et al. (2010) Matrix metalloproteinases are modifiers of huntingtin proteolysis and toxicity in Huntington's disease. Neuron, 67, 199-212.
18. Thompson, L.M., Aiken, C.T., Kaltenbach, L.S., Agrawal, N., Illes, K., Khoshnan, A., Martinez-Vincente, M., Arrasate, M., O'Rourke, J.G., Khashwji, H. et al. (2009) IKK phosphorylates Huntingtin and targets it for degradation by the proteasome and lysosome. J. Cell Biol., 187, 1083-1099.
19. Gu, X., Greiner, E.R., Mishra, R., Kodali, R., Osmand, A., Finkbeiner, S., Steffan, J.S., Thompson, L.M., Wetzel, R. and Yang, X.W. (2009) Serines 13 and 16 are critical determinants of full-length human mutant huntingtin induced disease pathogenesis in HD mice. Neuron, 64, 828-840.
20. Wheeler, V.C., White, J.K., Gutekunst, C.A., Vrbanac, V., Weaver, M., Li, X.J., Li, S.H., Yi, H., Vonsattel, J.P., Gusella, J.F. et al. (2000) Early phenotypes that presage late-onset neurodegenerative disease allow testing of modifiers in Hdh CAG knock-in mice. Hum. Mol. Genet., 11, 633-640.
21. Jeong, H., Then, F., Melia, T.J. Jr, Mazzulli, J.R., Cui, L., Savas, J.N., Voisine, C., Paganetti, P., Tanese, N., Hart, A.C. et al. (2009) Acetylation targets mutant huntingtin to autophagosomes for degradation. Cell, 137, 60-72.
22. Godin, J.D., Colombo, K., Molina-Calavita, M., Keryer, G., Zala, D., Charrin, B.C., Dietrich, P., Volvert, M.L., Guillemot, F., Dragatsis, I. et al. (2010) Huntingtin is required for mitotic spindle orientation and mammalian neurogenesis. Neuron, 67, 392-406.
23. Bangs, P., Burke, B., Powers, C., Craig, R., Purohit, A. and Doxsey, S. (1998) Functional analysis of Tpr: identification of nuclear pore complex association and nuclear localization domains and a role in mRNA export. J. Cell Biol., 143, 1801-1812.
24. Frosst, P., Guan, T., Subauste, C., Hahn, K. and Gerace, L. (2002) Tpr is localized within the nuclear basket of the pore complex and has a role in nuclear protein export. J. Cell Biol., 156, 617-630.
25. Cornett, J., Cao, F., Wang, C.E., Ross, C.A., Bates, G.P., Li, S.H. and Li, X.J. (2005) Polyglutamine expansion of huntingtin impairs its nuclear export. Nat. Genet., 37, 198-204.
26. Ben-Efraim, I., Frosst, P.D. and Gerace, L. (2009) Karyopherin binding interactions and nuclear import mechanism of nuclear pore complex protein Tpr. BMC Cell Biol., 10, 74.
27. Hickey, M.A., Kosmalska, A., Enayati, J., Cohen, R., Zeitlin, S., Levine, M.S. and Chesselet, M.F. (2008) Extensive early motor and non-motor behavioral deficits are followed by striatal neuronal loss in knock-in Huntington's disease mice. Neuroscience, 157, 280-295.
28. Schilling, G., Becher, M.W., Sharp, A.H., Jinnah, H.A., Duan, K., Kotzuk, J.A., Slunt, H.H., Ratovitski, T., Cooper, J.K., Jenkins, N.A. et al. (1999) Intranuclear inclusions and neuritic aggregates in transgenic mice expressing a mutant N-terminal fragment of huntingtin. Hum. Mol. Genet., 8, 397-407.
29. Woodman, B., Butler, R., Landles, C., Lupton, M.K., Tse, J., Hockly, E., Moffitt, H., Sathasivam, K. and Bates, G.P. (2007) The Hdh(Q150/Q150) knock-in mouse model of HD and the R6/2 exon 1 model develop comparable and widespread molecular phenotypes. Brain Res. Bull., 72, 83-97.
30. Heng, M.Y., Tallaksen-Greene, S.J., Detloff, P.J. and Albin, R.L. (2007) Longitudinal evaluation of the Hdh(CAG)150 knock-in murine model of Huntington's disease. J. Neurosci., 27, 8989-8998.
31. Yu, Z.X., Li, S.H., Evans, J., Pillarisetti, A., Li, H. and Li, X.J. (2003) Mutant huntingtin causes context-dependent neurodegeneration in mice with Huntington's disease. J. Neurosci., 23, 2193-2202.
32. Bradford, J., Shin, J.Y., Roberts, M., Wang, C.E., Li, X.J. and Li, S. (2009) Expression of mutant huntingtin in mouse brain astrocytes causes age-dependent neurological symptoms. Proc. Natl Acad. Sci. USA, 106, 22480-22485.
33. Yang, D., Wang, C.E., Zhao, B., Li, W., Ouyang, Z., Liu, Z., Yang, H., Fan, P., O'Neill, A., Gu, W. et al. (2010) Expression of Huntington's disease protein results in apoptotic neurons in the brains of cloned transgenic pigs. Hum. Mol. Genet., 19, 3983-3994.
34. Hackam, A.S., Singaraja, R., Wellington, C.L., Metzler, M., McCutcheon, K., Zhang, T., Kalchman, M. and Hayden, M.R. (1998) The influence of huntingtin protein size on nuclear localization and cellular toxicity. J. Cell Biol., 141, 1097-1105.
35. Peters, M.F., Nucifora, F.C. Jr, Kushi, J., Seaman, H.C., Cooper, J.K., Herring, W.J., Dawson, V.L., Dawson, T.M. and Ross, C.A. (1999) Nuclear targeting of mutant Huntingtin increases toxicity. Mol. Cell. Neurosci., 14, 121-128.
36. Chan, E.Y., Luthi-Carter, R., Strand, A., Solano, S.M., Hanson, S.A., DeJohn, M.M., Kooperberg, C., Chase, K.O., DiFiglia, M., Young, A.B. et al. (2002) Increased huntingtin protein length reduces the number of polyglutamine-induced gene expression changes in mouse models of Huntington's disease. Hum. Mol. Genet., 11, 1939-1951.
37. Schilling, G., Becher, M.W., Sharp, A.H., Jinnah, H.A., Duan, K., Kotzuk, J.A., Slunt, H.H., Ratovitski, T., Cooper, J.K., Jenkins, N.A. et al. (1999) Nuclear-targeting of mutant huntingtin fragments produces Huntington's disease-like phenotypes in transgenic mice. Hum. Mol. Genet., 13, 1599-1610.
38. Bangs, P., Burke, B., Powers, C., Craig, R., Purohit, A. and Doxsey, S. (1998) Contribution of nuclear and extranuclear polyQ to neurological phenotypes in mouse models of Huntington's disease. Hum. Mol. Genet., 14, 3065-3078.
39. Sawa, A., Nagata, E., Sutcliffe, S., Dulloor, P., Cascio, M.B., Ozeki, Y., Roy, S., Ross, C.A. and Snyder, S.H. (2005) Huntingtin is cleaved by caspases in the cytoplasm and translocated to the nucleus via perinuclear sites in Huntington's disease patient lymphoblasts. Neurobiol. Dis., 20, 267-274.
40. Davies, S.W., Turmaine, M., Cozens, B.A., DiFiglia, M., Sharp, A.H., Ross, C.A., Scherzinger, E., Wanker, E.E., Mangiarini, L. and Bates, G.P. (1997) Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation. Cell, 90, 537-548.
41. Zhou, H., Cao, F., Wang, Z., Yu, Z.X., Nguyen, H.P., Evans, J., Li, S.H. and Li, X.J. (2003) Huntingtin forms toxic NH2-terminal fragment complexes that are promoted by the age-dependent decrease in proteasome activity. J. Cell Biol., 163, 109-118.
42. Graham, R.K., Deng, Y., Slow, E.J., Haigh, B., Bissada, N., Lu, G., Pearson, J., Shehadeh, J., Bertram, L., Murphy, Z. et al. (2006) Cleavage at the caspase-6 site is required for neuronal dysfunction and degeneration due to mutant huntingtin. Cell, 125, 1179-1191.
43. Gray, M., Shirasaki, D.I., Cepeda, C., Andre, V.M., Wilburn, B., Lu, X.H., Tao, J., Yamazaki, I., Li, S.H., Sun, Y.E. et al. (2008) Full-length human mutant huntingtin with a stable polyglutamine repeat can elicit progressive and selective neuropathogenesis in BACHD mice. J. Neurosci., 28, 6182-6195.
44. Williams, A.J. and Paulson, H.L. (2008) Polyglutamine neurodegeneration: protein misfolding revisited. Trends Neurosci., 31, 521-528.
45. Duvick, L., Barnes, J., Ebner, B., Agrawal, S., Andresen, M., Lim, J., Giesler, G.J., Zoghbi, H.Y. and Orr, H.T. (2010) SCA1-like disease in mice expressing wild-type ataxin-1 with a serine to aspartic acid replacement at residue 776. Neuron, 67, 929-935.
46. Anne, S.L., Saudou, F. and Humbert, S. (2007) Phosphorylation of huntingtin by cyclin-dependent kinase 5 is induced by DNA damage and regulates wild-type and mutant huntingtin toxicity in neurons. J. Neurosci., 27, 7318-7328.
47. Colin, E., Zala, D., Liot, G., Rangone, H., Borrell-Pages, M., Li, X.J., Saudou, F. and Humbert, S. (2008) Huntingtin phosphorylation acts as a molecular switch for anterograde/retrograde transport in neurons. EMBO J., 27, 2124-2134.
48. Aiken, C.T., Steffan, J.S., Guerrero, C.M., Khashwji, H., Lukacsovich, T., Simmons, D., Purcell, J.M., Menhaji, K., Zhu, Y.Z., Green, K. et al. (2009) Phosphorylation of threonine 3: implications for Huntingtin aggregation and neurotoxicity. J. Biol. Chem., 284, 29427-29436.
49. Wang, Y., Lin, F. and Qin, Z.H. (2010) The role of post-translational modifications of huntingtin in the pathogenesis of Huntington's disease. Neurosci. Bull., 26, 153-162.
50. Wang, C.E., Zhou, H., McGuire, J.R., Cerullo, V., Lee, B., Li, S.H. and Li, X.J. (2008) Suppression of neuropil aggregates and neurological symptoms by an intracellular antibody implicates the cytoplasmic toxicity of mutant huntingtin. J. Cell Biol., 181, 803-816.