Transgenic mice expressing caspase-6-derived Nterminal fragments of mutant huntingtin develop neurologic abnormalities with predominant cytoplasmic inclusion pathology composed largely of a smaller proteolytic derivative

Human Molecular Genetics

Volumn 20, Issue 14, 2011, Pages 2770-2782

  Tebbenkamp, Andrew T N ^a   Green, Cameron ^a,b   Xu, Guilian ^a,b   Denovan Wright, Eileen M ^c   Rising, Aaron C ^a   Fromholt, Susan E ^a,b   Brown, Hilda H ^a,b   Swing, Debbie ^d   Mandel, Ronald J ^a   Tessarollo, Lino ^d   Borchelt, David R ^a,b  

^a UNIVERSITY OF FLORIDA COLLEGE OF MEDICINE   (United States)

^b UNIVERSITY OF FLORIDA   (United States)

^c DALHOUSIE UNIVERSITY   (Canada)

^d NATIONAL CANCER INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIBODY; CASPASE 6; EPITOPE; GLUTAMINE; HUNTINGTIN; MESSENGER RNA; PROTEINASE;

AMINO TERMINAL SEQUENCE; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; ATAXIA; BIOCHEMISTRY; BODY WEIGHT; BRAIN WEIGHT; CELL INCLUSION; CONTROLLED STUDY; CORPUS STRIATUM; DYSKINESIA; HUNTINGTON CHOREA; MOTOR PERFORMANCE; MOUSE; NEUROLOGIC DISEASE; NONHUMAN; PHENOTYPE; PRIORITY JOURNAL; PROTEIN DEGRADATION; RESTRICTION FRAGMENT; ROTAROD TEST; TRANSGENIC MOUSE;

AMINO ACID SUBSTITUTION; ANIMALS; ATAXIA; CASPASE 6; CORPUS STRIATUM; GENE EXPRESSION; HUMANS; HUNTINGTON DISEASE; INCLUSION BODIES; MICE; MICE, TRANSGENIC; MUTATION, MISSENSE; NERVE TISSUE PROTEINS; NUCLEAR PROTEINS; RNA, MESSENGER; ROTAROD PERFORMANCE TEST;

MUS; MUS MUSCULUS;

EID: 79959802847     PISSN: 09646906     EISSN: 14602083     Source Type: Journal    
DOI: 10.1093/hmg/ddr176     Document Type: Article

References (43)

1. Huntington's Disease Collaborative Research Group. (1993) A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell, 72, 971-983.
2. Brinkman, R.R., Mezei, M.M., Theilmann, J., Almqvist, E. and Hayden, M.R. (1997) The likelihood of being affected with Huntington disease by a particular age, for a specific CAG size. Am. J. Hum. Genet., 60, 1202-1210.
3. Walker, F.O. (2007) Huntington's disease. Lancet, 369, 218-228.
4. de la Monte, S.M., Vonsattel, J.-P. and Richardson, E.P. (1988) Morphometric demonstration of atrophic changes in the cerebral cortex, white matter, and neostriatum in Huntington's disease. J. Neuropathol. Exp. Neurol., 47, 516-525.
5. Myers, R.H., Vonsattel, J.P., Stevens, T.J., Cupples, L.A., Richardson, E.P., Martin, J.B. and Bird, E.D. (1988) Clinical and neuropathologic assessment of severity in Huntington's disease. Neurology, 38, 341-347.
6. 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.
7. Becher, M.W., Kotzuk, J.A., Sharp, A.H., Davies, S.W., Bates, G.P., Price, D.L. and Ross, C.A. (1998) Intranuclear neuronal inclusions in Huntington's disease and dentatorubral and pallidoluysian atrophy: correlation between the density of inclusions and IT15 CAG triplet repeat length. Neurobiol. Dis., 4, 387-397.
8. 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.
9. Herndon, E.S., Hladik, C.L., Shang, P., Burns, D.K., Raisanen, J. and White, C.L. III (2009) Neuroanatomic profile of polyglutamine immunoreactivity in Huntington disease brains. J. Neuropathol. Exp. Neurol., 68, 250-261.
10. Sieradzan, K.A., Mechan, A.O., Jones, L., Wanker, E.E., Nukina, N. and Mann, D.M. (1999) Huntington's disease intranuclear inclusions contain truncated, ubiquitinated huntingtin protein. Exp. Neurol., 156, 92-99.
11. Lunkes, A., Lindenberg, K.S., Ben Haiem, L., Weber, C., Devys, D., Landwehrmeyer, G.B., Mandel, J.L. and Trottier, Y. (2002) Proteases acting on mutant huntingtin generate cleaved products that differentially build up cytoplasmic and nuclear inclusions. Mol. Cell, 10, 259-269.
12. Schilling, G., Klevytska, A., Tebbenkamp, A.T., Juenemann, K., Cooper, J., Gonzales, V., Slunt, H., Poirer, M., Ross, C.A. and Borchelt, D.R. (2007) Characterization of huntingtin pathologic fragments in human Huntington disease, transgenic mice, and cell models. J. Neuropathol. Exp. Neurol., 66, 313-320.
13. Ratovitski, T., Gucek, M., Jiang, H., Chighladze, E., Waldron, E., D'Ambola, J., Hou, Z., Liang, Y., Poirer, M.A., Hirschhorn, R.R. et al. (2009) Mutant Huntingtin N-terminal fragments of specific size mediate aggregation and toxicity in neuronal cells. J. Biol. Chem., 284, 10855-10867.
14. Kegel, K.B., Sapp, E., Alexander, J., Reeves, P., Bleckmann, D., Sobin, L., Masso, N., Valencia, A., Jeong, H., Krainc, D. et al. (2010) Huntingtin cleavage product A forms in neurons and is reduced by gamma-secretase inhibitors. Mol. Neurodegener., 5, 58.
15. Wellington, C.L., Singaraja, R., Ellerby, L., Savill, J., Roy, S., Leavitt, B., Cattaneo, E., Hackam, A., Sharp, A., Thornberry, N. et al. (2000) Inhibiting caspase cleavage of huntingtin reduces toxicity and aggregate formation in neuronal and nonneuronal cells. J. Biol. Chem., 275, 19831-19838.
16. Wellington, C.L., Ellerby, L.M., Gutekunst, C.A., Rogers, D., Warby, S., Graham, R.K., Loubser, O., van Raamsdonk, J., Singaraja, R., Yang, Y.Z. et al. (2002) Caspase cleavage of mutant huntingtin precedes neurodegeneration in Huntington's disease. J. Neurosci., 22, 7862-7872.
17. Gafni, J., Hermel, E., Young, J.E., Wellington, C.L., Hayden, M.R. and Ellerby, L.M. (2004) Inhibition of calpain cleavage of huntingtin reduces toxicity: accumulation of calpain/caspase fragments in the nucleus. J. Biol. Chem., 279, 20211-20220.
18. 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.
19. 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.
20. Warby, S.C., Doty, C.N., Graham, R.K., Carroll, J.B., Yang, Y.Z., Singaraja, R.R., Overall, C.M. and Hayden, M.R. (2008) Activated caspase-6 and caspase-6-cleaved fragments of huntingtin specifically colocalize in the nucleus. Hum. Mol. Genet., 17, 2390-2404.
21. Graham, R.K., Deng, Y., Carroll, J., Vaid, K., Cowan, C., Pouladi, M.A., Metzler, M., Bissada, N., Wang, L., Faull, R.L. et al. (2010) Cleavage at the 586 amino acid caspase-6 site in mutant huntingtin influences caspase-6 activation in vivo. J. Neurosci., 30, 15019-15029.
22. Tebbenkamp, A.T., Swing, D., Tessarollo, L. and Borchelt, D.R. (2011) Premature death and neurologic abnormalities in transgenic mice expressing a mutant huntingtin exon-2 fragment. Hum. Mol. Genet., epub.
23. Mangiarini, L., Sathasivam, K., Seller, M., Cozens, B., Harper, A., Hetherington, C., Lawton, M., Trottier, Y., Lehrach, H., Davies, S.W. et al. (1996) Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell, 87, 493-506.
24. Carter, R.J., Lione, L.A., Humby, T., Mangiarini, L., Mahal, A., Bates, G.P., Dunnett, S.B. and Morton, A.J. (1999) Characterization of progressive motor deficits in mice transgenic for the human Huntington's disease mutation. J. Neurosci., 19, 3248-3257.
25. 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 pathology in transgenic mice expressing a mutant N-terminal fragment of huntingtin. Hum. Mol. Genet., 8, 397-407.
26. Borchelt, D.R., Davis, J., Fischer, M., Lee, M.K., Slunt, H.H., Ratovitsky, T., Regard, J., Copeland, N.G., Jenkins, N.A., Sisodia, S.S. et al. (1996) A vector for expressing foreign genes in the brains and hearts of transgenic mice. Genet. Anal. (Biomed. Eng.), 13, 159-163.
27. Schilling, G., Jinnah, H.A., Gonzales, V., Coonfield, M.L., Kim, Y., Wood, J.D., Price, D.L., Li, X.J., Jenkins, N., Copeland, N. et al. (2001) Distinct behavioral and neuropathological abnormalities in transgenic mouse models of HD and DRPLA. Neurobiol. Dis., 8, 405-418.
28. Scherzinger, E., Sittler, A., Schweiger, K., Heiser, V., Lurz, R., Hasenbank, R., Lehrach, H. and Wanker, E.E. (1999) Self-assembly of polyglutamine-containing huntingtin fragments into amyloid-like fibrils: implications for Huntington's disease pathology. Proc. Natl Acad. Sci. USA, 96, 4604-4609.
29. Chen, S., Berthelier, V., Yang, W. and Wetzel, R. (2001) Polyglutamine aggregation behavior in vitro supports a recruitment mechanism of cytotoxicity. J. Mol. Biol., 311, 173-182.
30. Diaz-Hernandez, M., Torres-Peraza, J., Salvatori-Abarca, A., Moran, M.A., Gomez-Ramos, P., Alberch, J. and Lucas, J.J. (2005) Full motor recovery despite striatal neuron loss and formation of irreversible amyloid-like inclusions in a conditional mouse model of Huntington's disease. J. Neurosci., 25, 9773-9781.
31. Vonsattel, J.P.G. and DiFiglia, M. (1998) Huntington disease. J. Neuropath. Exp. Neurol., 57, 369-384.
32. 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.
33. Heng, M.Y., Duong, D.K., Albin, R.L., Tallaksen-Greene, S.J., Hunter, J.M., Lesort, M.J., Osmand, A., Paulson, H.L. and Detloff, P.J. (2010) Early autophagic response in a novel knock-in model of Huntington disease. Hum. Mol. Genet., 19, 3702-3720.
34. Luthi-Carter, R., Strand, A.D., Hanson, S.A., Kooperberg, C., Schilling, G., La Spada, A.R., Merry, D.E., Young, A.B., Ross, C.A., Borchelt, D.R. et al. (2002) Polyglutamine and transcription: gene expression changes shared by DRPLA and Huntington's disease mouse models reveal context-independent effects. Hum. Mol. Genet., 11, 1927-1937.
35. Hodges, A., Strand, A.D., Aragaki, A.K., Kuhn, A., Sengstag, T., Hughes, G., Elliston, L.A., Hartog, C., Goldstein, D.R., Thu, D. et al. (2006) Regional and cellular gene expression changes in human Huntington's disease brain. Hum. Mol. Genet., 15, 965-977.
36. Slow, E.J., van Raamsdonk, J., Rogers, D., Coleman, S.H., Graham, R.K., Deng, Y., Oh, R., Bissada, N., Hossain, S.M., Yang, Y.Z. et al. (2003) Selective striatal neuronal loss in a YAC128 mouse model of Huntington disease. Hum. Mol. Genet., 12, 1555-1567.
37. Wang, C.E., Tydlacka, S., Orr, A.L., Yang, S.H., Graham, R.K., Hayden, M.R., Li, S., Chan, A.W. and Li, X.J. (2008) Accumulation of N-terminal mutant huntingtin in mouse and monkey models implicated as a pathogenic mechanism in Huntington's disease. Hum. Mol. Genet., 17, 2738-2751.
38. Laemmli, U.K. (1970) Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature, 227, 680-685.
39. Schilling, G., Coonfield, M.L., Ross, C.A. and Borchelt, D.R. (2001) Coenzyme Q10 and remacemide hydrochloride amerliorate motor deficits in a Huntington's disease transgenic mouse model. Neurosci. Lett., 315, 149-153.
40. Luthi-Carter, R., Strand, A., Peters, N.L., Solano, S.M., Hollingsworth, Z.R., Menon, A.S., Frey, A.S., Spektor, B.S., Penney, E.B., Schilling, G. et al. (2000) Decreased expression of striatal signaling genes in a mouse model of Huntington's disease. Hum. Mol. Genet., 9, 1259-1271.
41. Rodriguez-Lebron, E., Denovan-Wright, E.M., Nash, K., Lewin, A.S. and Mandel, R.J. (2005) Intrastriatal rAAV-mediated delivery of anti-huntingtin shRNAs induces partial reversal of disease progression in R6/1 Huntington's disease transgenic mice. Mol. Ther., 12, 618-633.
42. Hebb, A.L., Robertson, H.A. and Denovan-Wright, E.M. (2004) Striatal phosphodiesterase mRNA and protein levels are reduced in Huntington's disease transgenic mice prior to the onset of motor symptoms. Neuroscience, 123, 967-981.
43. Hu, H., McCaw, E.A., Hebb, A.L., Gomez, G.T. and Denovan-Wright, E.M. (2004) Mutant huntingtin affects the rate of transcription of striatum-specific isoforms of phosphodiesterase 10A. Eur. J. Neurosci., 20, 3351-3363.