Evidence for both the nucleus and cytoplasm as subcellular sites of pathogenesis in huntington's disease in cell culture and in transgenic mice expressing mutant huntingtin

Philosophical Transactions of the Royal Society B: Biological Sciences

Volumn 354, Issue 1386, 1999, Pages 1047-1055

  Hackam, Abigail S ^a,b   Hodgson, J Graeme ^a,b   Singaraja, Roshni ^a,b   Zhang, Taiqi ^a,b   Gan, Lu ^a,b   Gutekunst, Claire Anne ^c   Hersch, Steven M ^c   Hayden, Michael R ^a,b  

^a Centre for Molecular Medicine and Therapeutics   (Canada)

^b UNIVERSITY OF BRITISH COLUMBIA   (Canada)

^c EMORY UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Aggregates; Animal model; Huntington's disease; In vitro; Pathogenesis

Indexed keywords

AMINO TERMINAL SEQUENCE; APOPTOSIS; CELL CULTURE; CELL NUCLEUS; CYTOSOL; GENE MUTATION; HUNTINGTIN; HUNTINGTON CHOREA; PATHOGENESIS; PROTEIN AGGREGATION; PROTEIN HYDROLYSIS; PROTEIN LOCALIZATION; TRANSGENIC MOUSE;

ANIMALIA; MUS MUSCULUS;

EID: 0033614773     PISSN: 09628436     EISSN: None     Source Type: Journal    
DOI: 10.1098/rstb.1999.0457     Document Type: Article

References (45)

1. Andrew, S. E., Goldberg, Y. P. & Hayden, M. R. 1997 Commentary: rethinking genotype and phenotype correlations in polyglutamine expansion disorders. Hum. Mol. Genet. 6, 2005-2010.
2. Becher, M. W., Kotzuk, J. A., Sharp, A. H., Davies, S. W., Bates, G. P., Price, D. L. & Ross, C. A. 1998 Intranuclear neuronal inclusions in Huntington's disease and dentatorubral and palidoluysian atrophy: correlation between the density of inclusions and IT15 CAG triplet repeat length. Neurobiol. Dis. 4, 387-397.
3. Bots, G. T. & Bruyn, G. W. 1981 Neuropathological changes of the nucleus accumbens in Huntington's chorea. Acta Neuropathol. 55, 21-22.
4. Burke, J. R., Enghild, J. J., Martin, M. E., Jou, Y. S., Myers, R. M., Roses, A. D., Vance, J. M. & Strittmatter, W. J. 1996 Huntingtin and DRPLA proteins selectively interact with the enzyme GAPDH. Nature Med. 2, 347-350.
5. Butler, R., Leigh, P. N., McPhaul, M. J. & Gallo, J.-M. 1998 Truncated forms of the androgen receptor are associated with polyglutamine expansion in X-linked spinal and bulbar muscular atrophy. Hum. Mol. Genet. 7, 121-127.
6. Carmichael, J., DeGraff, W. G., Gazdar, A. F., Minna, J. D. & Mitchell, J. B. 1987 Evaluation of a tetrazolium-based semi-automated colorimetric assay: assessment of chemosensitivity testing. Cancer Res. 47, 936-942.
7. Cooper, J. K. (and 12 others) 1998 Truncated N-terminal fragments of huntingtin with expanded glutamine repeats form nuclear and cytoplasmic aggregates in cell culture. Hum. Mol. Genet. 7, 783-790.
8. Cummings, C. J., Mancini, M. A., Antalffy, B., DeFranco, D. B., Orr, H. T. & Zoghbi, H. Y. 1998 Chaperone suppression of aggregation and altered subcellular proteasome localization imply protein misfolding in SCA1. Nature Genet. 19, 148-154.
9. Davies, S. W., Turmaine, M., Cozens, B. A., DiFiglia, M., Sharp, A. H., Ross, C. A., Scherzinger, E., Wanker, E. E., Mangiarini, L. & Bates, G. P. 1997 Formation of neuronal intranuclear inclusions (NII) underlies the neurological dysfunction in mice transgenic for the HD mutation. Cell 90, 537-348.
10. DiFiglia, M., Sapp, E., Chase, K. O., Davies, S. W., Bates, G. P., Vonsattel, J. P. & Aronin, N. 1997 Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science 277, 1990-1993.
11. Ellerby, L. M. (and 10 others) 1999a Kennedy's disease: caspase cleavage of the androgen receptor is a crucial event in cytotoxicity. J. Neurochem. 72, 185-195.
12. Ellerby, L. M. (and 11 others) 1999b Cleavage of atrophin-1 at caspase site aspartic acid 109 modulates cytotoxicity. J. Cell Biol. 274, 8730-8736.
13. Goldberg, Y. P. (and 10 others) 1996 Cleavage of huntingtin by apopain, a proapoptotic cysteine protease, is modulated by the polyglutamine tract. Nature Genet. 13, 442-449.
14. Gourfinkel-An, I., Cancel, G., Duyckaerts, C., Faucheux, B., Hauw, J.-J., Trottier, Y., Brice, A., Agid, Y. & Hirsch, E. C. 1998 Neuronal distribution of intranuclear inclusions in Huntington's disease with adult onset. NeuroReport 9, 1823-1826.
15. Görlich, D. & Mattaj, I. W. 1996 Nucleocytoplasmic transport. Science 271, 1513-1518.
16. Green, D. R. & Reed, J. C. 1998 Mitochondria and apoptosis. Science 281, 1309-1312.
17. Hackam, A. S., Singaraja, R., Wellington, C. L., Metzler, M., McCutcheon, K., Zhang, T., Kalchman, M. & Hayden, M. R. 1998a The influence of huntingtin protein size on nuclear localization and cellular toxicity. J. Cell Biol. 141, 1097-1105.
18. Hackam, A. S., Wellington, C. L. & Hayden, M. R. 1998b The fatal attraction of polyglutamine-containing proteins. Clin. Genet. 53, 233-242.
19. Hackam, A. S., Singaraja, R., Zhang, T., Gan, L. & Hayden, M. R. 1999 In vitro evidence for both the nucleus and cytoplasm as subcellular sites of pathogenesis in Huntington disease. Hum. Mol. Genet. 8, 25-33.
20. Hodgson, J. G. (and 18 others) 1999 A YAC mouse model for Huntington's disease with full-length mutant huntington, cytoplasmic toxicity and striatal neurodegeneration. Neuron. (In the press.)
21. Holmberg, M. (and 10 others) 1998 Spinocerebellar ataxia type 7 (SCA7): a neurodegenerative disorder with neuronal intranuclear inclusions. Hum. Mol. Genet. 7, 913-918.
22. Igarashi, S. (and 18 others) 1998 Suppression of aggregate formation and apoptosis by transglutaminase inhibitors in cells expressing truncated DRPLA protein with an expanded polyglutamine stretch. Nature Genet. 18, 111-117.
23. Kalchman, M. A. (and 13 others) 1997 HIP1, a human homolog of S. cerevisiae, Sla2p, interacts with membrane-associated huntingtin in the brain. Nature Genet. 16, 44-53.
24. Klement, I. A., Skinner, P. J., Kaytor, M. D., Yi, H., Hersch, S. M., Clark, H. B., Zoghbi, H. Y. & Orr, H. T. 1998 Ataxin-1 nuclear localization and aggregation: role in polyglutamine-induced disease in SCA1 transgenic mice. Cell 95, 41-53.
25. Li, M., Nakagomi, Y., Kobayashi, Y., Merry, D, E., Tanaka, F., Doyu, M., Mitsuma, T., Hashizume, Y., Fischbeck, K. H. & Sobue, G. 1998 Non-neural inclusions of androgen receptor protein in spinal and bulbar muscular atrophy. Am. J. Pathol. 153, 695-701.
26. Li, S.-H. & Li, X.-J. 1998 Aggregation of N-terminal huntingtin is dependent on the length of its glutamine repeats. Hum. Mol. Genet. 7, 777-782.
27. Li, X. J., Li, S. H., Sharp, A. H., Nucifora Jr, F. C., Schilling, G., Lanahan, A., Worley, P., Snyder, S. H. & Ross, C. A. 1995 A huntingtin-associated protein enriched in brain with implications for pathology. Nature 378, 398-402.
28. Lunkes, A. & Mandel, J.-L. 1997 Polyglutamines, nuclear inclusions and neurodegeneration. Nature Med. 8, 1201-1202.
29. Lunkes, A. & Mandel, J.-L. 1998 A cellular model that recapitulates major pathogenic steps of Huntington's disease. Hum. Mol. Genet. 7, 1355-1361.
30. Martindale, D. (and 11 others) 1998 Length of the protein and polyglutamine tract influence localization and frequency of intracellular aggregates of huntingtin. Nature Genet. 18, 150-154.
31. Matilla, A., Koshy, B. T., Cummings, C. J., Isobe, T., Orr, H. T. & Zoghbi, H. Y. 1997 The cerebellar leucine-rich acidic nuclear protein interacts with ataxin-1. Nature 389, 974-978.
32. Merry, D. E., Kobayashi, Y., Bailey, C. K., Taye, A. A. & Fischbeck, K. H. 1998 Cleavage, aggregation and toxicity of the expanded androgen receptor in spinal and bulbar muscular atrophy. Hum. Mol. Genet. 7, 693-701.
33. Miyashita, T., Okamura-Oho, Y., Mito, Y., Nagafuchi, S. & Yamada, M. 1997 Dentatorubral pallidoluysian atrophy (DRPLA) protein is cleaved by caspase-3 during apoptosis. J. Biol. Chem. 272, 29238-29242.
34. Ordway, J. M. (and 11 others) 1997 Ectopically expressed CAG repeats cause intranuclear inclusions and a progressive late onset neurological phenotype in the mouse. Cell 91, 753-763.
35. Paulson, H. L., Perez, M. K., Trottier, Y., Trojanowski, J. Q., Subramony, S. H., Das, S. S., Vig, P., Mandel, J.-L., Fischbeck, K. H. & Pittman, R. N. 1997 Intranuclear inclusions of expanded polyglutamine protein in spinocerebellar ataxia type 3. Neuron 19, 333-344.
36. Ross, C. 1997 Intranuclear neuronal inclusions: a common pathogenic mechanism for glutamine-repeat neurodegenerative diseases? Neuron 19, 1147-1150.
37. Sapp, E., Schwarz, C., Chase, K., Bhide, P. G., Young, A. B., Penney, J., Vonsattel, J. P., Aronin, N. & DiFiglia, M. 1997 Huntingtin localisation in brains of normal and Huntington's disease patients. Ann. Neurol. 42, 604-612.
38. Saudou, F., Finkbeiner, S., Devys, D. & Greenberg, M. E. 1998 Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions. Cell 95, 55-66.
39. Skinner, P. J., Koshy, B. T., Cummings, C. J., Klement, I. A., Helin, K., Servadio, A., Zoghbi, H. Y. & Orr, H. T. 1997 Ataxin-1 with an expanded glutamine tract alters nuclear matrix-associated structures. Nature 389, 971-974.
40. Stevanin, G. (and 17 others) 1996 Screening for proteins with polyglutamine expansions in autosomal dominant cerebellar ataxias. Hum. Mol. Genet. 5, 1887-1892.
41. Tait, D., Riccio, M., Sittler, A., Scherzinger, E., Santi, S., Ognibene, A., Maraldi, N. M., Lehrach, H. & Wanker, E. E. 1998 Ataxin-3 is transported into the nucleus and associates with the nuclear matrix. Hum. Mol. Genet. 7, 991-997.
42. Tellez-Nagel, I., Johnson, A. B. & Terry, R. D. 1971 Studies on brain biopsies of patients with Huntington's chorea. J. Neuropathol. Exp. Neurol. 33, 308-332.
43. Trottier, Y, (and 12 others) 1995 Polyglutamine expansion as a pathological epitope in Huntington's disease and four dominant cerebellar ataxias. Nature 378, 403-406.
44. Warrick, J. M., Paulson, M. L., Gladys, L., Gray-Board, G. L., Bui, Q. T., Fischbeck, K. H., Pittman, R. N. & Bonini, N. M. 1998 Expanded polyglutamine protein forms nuclear inclusions and causes neural degeneration in Drosophila. Cell 93, 939-949.
45. Wellington, C. L. (and 20 others) 1998 Caspase cleavage of gene products associated with triplet expansion disorders generates truncated fragments containing the polyglutamine tract. J. Biol. Chem. 273, 9159-9167.