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Science 23 March 2001:
Vol. 291. no. 5512, pp. 2423 - 2428
DOI: 10.1126/science.1056784
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Reports

Interference by Huntingtin and Atrophin-1 with CBP-Mediated Transcription Leading to Cellular Toxicity

Frederick C. Nucifora Jr.,12 Masayuki Sasaki,3 Matthew F. Peters,1 Hui Huang,3 Jillian K. Cooper,1 Mitsunori Yamada,7 Hitoshi Takahashi,7 Shoji Tsuji,7 Juan Troncoso,6 Valina L. Dawson,2345 Ted M. Dawson,234* Christopher A. Ross124*

Expanded polyglutamine repeats have been proposed to cause neuronal degeneration in Huntington's disease (HD) and related disorders, through abnormal interactions with other proteins containing short polyglutamine tracts such as the transcriptional coactivator CREB binding protein, CBP. We found that CBP was depleted from its normal nuclear location and was present in polyglutamine aggregates in HD cell culture models, HD transgenic mice, and human HD postmortem brain. Expanded polyglutamine repeats specifically interfere with CBP-activated gene transcription, and overexpression of CBP rescued polyglutamine-induced neuronal toxicity. Thus, polyglutamine-mediated interference with CBP-regulated gene transcription may constitute a genetic gain of function, underlying the pathogenesis of polyglutamine disorders.

1 Division of Neurobiology, Department of Psychiatry,
2 The Program in Cellular and Molecular Medicine,
3 Department of Neurology,
4 Department of Neuroscience,
5 Department of Physiology,
6 Department of Neuropathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205-2196, USA.
7 Department of Pathology and Neurology, Brain Research Institute, Niigata University, 1-757 Asahimachi, Niigata 951-8585, Japan.
*   To whom correspondence should be addressed. E-mail: tdawson{at}jhmi.edu and caross{at}jhu.edu

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   Abstract »    Full Text »    PDF »
DNA damage induced by polyglutamine-expanded proteins.
P. Giuliano, T. de Cristofaro, A. Affaitati, G. M. Pizzulo, A. Feliciello, C. Criscuolo, G. De Michele, A. Filla, E. V. Avvedimento, and S. Varrone (2003)
Hum. Mol. Genet. 12, 2301-2309
   Abstract »    Full Text »    PDF »
Stimulation of NeuroD activity by huntingtin and huntingtin-associated proteins HAP1 and MLK2.
E. Marcora, K. Gowan, and J. E. Lee (2003)
PNAS 100, 9578-9583
   Abstract »    Full Text »    PDF »
Ubiquitin-mediated sequestration of normal cellular proteins into polyglutamine aggregates.
K. M. Donaldson, W. Li, K. A. Ching, S. Batalov, C.-C. Tsai, and C. A. P. Joazeiro (2003)
PNAS 100, 8892-8897
   Abstract »    Full Text »    PDF »
Expansion of the polyQ repeat in ataxin-2 alters its Golgi localization, disrupts the Golgi complex and causes cell death.
D. P. Huynh, H.-T. Yang, H. Vakharia, D. Nguyen, and S. M. Pulst (2003)
Hum. Mol. Genet. 12, 1485-1496
   Abstract »    Full Text »    PDF »
Dentatorubral-pallidoluysian atrophy protein is phosphorylated by c-Jun NH2-terminal kinase.
Y. Okamura-Oho, T. Miyashita, K. Nagao, S. Shima, Y. Ogata, T. Katada, H. Nishina, and M. Yamada (2003)
Hum. Mol. Genet. 12, 1535-1542
   Abstract »    Full Text »    PDF »
Aberrant histone acetylation, altered transcription, and retinal degeneration in a Drosophila model of polyglutamine disease are rescued by CREB-binding protein.
J. P. Taylor, A. A. Taye, C. Campbell, P. Kazemi-Esfarjani, K. H. Fischbeck, and K.-T. Min (2003)
Genes & Dev. 17, 1463-1468
   Abstract »    Full Text »    PDF »
Prevention of polyglutamine oligomerization and neurodegeneration by the peptide inhibitor QBP1 in Drosophila.
Y. Nagai, N. Fujikake, K. Ohno, H. Higashiyama, H. A. Popiel, J. Rahadian, M. Yamaguchi, W. J. Strittmatter, J. R. Burke, and T. Toda (2003)
Hum. Mol. Genet. 12, 1253-1259
   Abstract »    Full Text »    PDF »
Polyglutamine Expansion Induces a Protein-damaging Stress Connecting Heat Shock Protein 70 to the JNK Pathway.
K. Merienne, D. Helmlinger, G. R. Perkin, D. Devys, and Y. Trottier (2003)
J. Biol. Chem. 278, 16957-16967
   Abstract »    Full Text »    PDF »
Nuclear Localization of a Non-caspase Truncation Product of Atrophin-1, with an Expanded Polyglutamine Repeat, Increases Cellular Toxicity.
F. C. Nucifora Jr., L. M. Ellerby, C. L. Wellington, J. D. Wood, W. J. Herring, A. Sawa, M. R. Hayden, V. L. Dawson, T. M. Dawson, and C. A. Ross (2003)
J. Biol. Chem. 278, 13047-13055
   Abstract »    Full Text »    PDF »
Apoptosis and Caspases in Neurodegenerative Diseases.
R. M. Friedlander (2003)
N. Engl. J. Med. 348, 1365-1375
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PQBP-1 transgenic mice show a late-onset motor neuron disease-like phenotype.
T. Okuda, H. Hattori, S. Takeuchi, J. Shimizu, H. Ueda, J. J. Palvimo, I. Kanazawa, H. Kawano, M. Nakagawa, and H. Okazawa (2003)
Hum. Mol. Genet. 12, 711-725
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Homozygosity for CAG mutation in Huntington disease is associated with a more severe clinical course.
F. Squitieri, C. Gellera, M. Cannella, C. Mariotti, G. Cislaghi, D. C. Rubinsztein, E. W. Almqvist, D. Turner, A.-C. Bachoud-Levi, S. A. Simpson, et al. (2003)
Brain 126, 946-955
   Abstract »    Full Text »    PDF »
Histone deacetylase inhibitors prevent oxidative neuronal death independent of expanded polyglutamine repeats via an Sp1-dependent pathway.
H. Ryu, J. Lee, B. A. Olofsson, A. Mwidau, A. Dedeoglu, M. Escudero, E. Flemington, J. Azizkhan-Clifford, R. J. Ferrante, and R. R. Ratan (2003)
PNAS 100, 4281-4286
   Abstract »    Full Text »    PDF »
Heat Shock Protein 70 Chaperone Overexpression Ameliorates Phenotypes of the Spinal and Bulbar Muscular Atrophy Transgenic Mouse Model by Reducing Nuclear-Localized Mutant Androgen Receptor Protein.
H. Adachi, M. Katsuno, M. Minamiyama, C. Sang, G. Pagoulatos, C. Angelidis, M. Kusakabe, A. Yoshiki, Y. Kobayashi, M. Doyu, et al. (2003)
J. Neurosci. 23, 2203-2211
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Cdc42-interacting protein 4 binds to huntingtin: Neuropathologic and biological evidence for a role in Huntington's disease.
S. Holbert, A. Dedeoglu, S. Humbert, F. Saudou, R. J. Ferrante, and C. Neri (2003)
PNAS 100, 2712-2717
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Specific progressive cAMP reduction implicates energy deficit in presymptomatic Huntington's disease knock-in mice.
S. Gines, I. S. Seong, E. Fossale, E. Ivanova, F. Trettel, J. F. Gusella, V. C. Wheeler, F. Persichetti, and M. E. MacDonald (2003)
Hum. Mol. Genet. 12, 497-508
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Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, ameliorates motor deficits in a mouse model of Huntington's disease.
E. Hockly, V. M. Richon, B. Woodman, D. L. Smith, X. Zhou, E. Rosa, K. Sathasivam, S. Ghazi-Noori, A. Mahal, P. A. S. Lowden, et al. (2003)
PNAS 100, 2041-2046
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Dysfunction of Wild-Type Huntingtin in Huntington disease.
E. Cattaneo (2003)
Physiology 18, 34-37
   Abstract »    Full Text »    PDF »


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