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Originally published in Science Express on 14 June 2001
Science 20 July 2001:
Vol. 293. no. 5529, pp. 493 - 498
DOI: 10.1126/science.1059581
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Reports

Loss of Huntingtin-Mediated BDNF Gene Transcription in Huntington's Disease

Chiara Zuccato,12 Andrea Ciammola,123 Dorotea Rigamonti,12 Blair R. Leavitt,4 Donato Goffredo,12 Luciano Conti,12 Marcy E. MacDonald,5 Robert M. Friedlander,6 Vincenzo Silani,23 Michael R. Hayden,4 Tõnis Timmusk,7 Simonetta Sipione,12 Elena Cattaneo12

Huntingtin is a 350-kilodalton protein of unknown function that is mutated in Huntington's disease (HD), a neurodegenerative disorder. The mutant protein is presumed to acquire a toxic gain of function that is detrimental to striatal neurons in the brain. However, loss of a beneficial activity of wild-type huntingtin may also cause the death of striatal neurons. Here we demonstrate that wild-type huntingtin up-regulates transcription of brain-derived neurotrophic factor (BDNF), a pro-survival factor produced by cortical neurons that is necessary for survival of striatal neurons in the brain. We show that this beneficial activity of huntingtin is lost when the protein becomes mutated, resulting in decreased production of cortical BDNF. This leads to insufficient neurotrophic support for striatal neurons, which then die. Restoring wild-type huntingtin activity and increasing BDNF production may be therapeutic approaches for treating HD.

1 Department of Pharmacological Sciences, University of Milano, Via Balzaretti 9, 20133 Milano, Italy.
2 Center of Excellence on Neurodegenerative Diseases, University of Milano, Italy.
3 Centro "Dino Ferrari," Department of Neurological Sciences, University of Milan Medical School, IRCCS Ospedale Maggiore, Milano, Italy.
4 Centre for Molecular Medicine and Therapeutic Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
5 Molecular Neurogenetics Unit, Massachusetts General Hospital, Charlestown, MA 02129, USA.
6 Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
7 Program of Molecular Neuroscience, Institute of Biotechnology, Helsinki, Finland, and Department of Developmental Neuroscience, Biomedical Center, Uppsala University, Uppsala, Sweden.
To whom correspondence should be addressed. E-mail: elena.cattaneo{at}unimi.it

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   Abstract »    Full Text »    PDF »
Mismatch repair gene Msh2 modifies the timing of early disease in HdhQ111 striatum.
V. C. Wheeler, L.-A. Lebel, V. Vrbanac, A. Teed, H. te Riele, and M. E. MacDonald (2003)
Hum. Mol. Genet. 12, 273-281
   Abstract »    Full Text »    PDF »
Dysfunction of Wild-Type Huntingtin in Huntington disease.
E. Cattaneo (2003)
Physiology 18, 34-37
   Abstract »    Full Text »    PDF »
Transient and Progressive Electrophysiological Alterations in the Corticostriatal Pathway in a Mouse Model of Huntington's Disease.
C. Cepeda, R. S. Hurst, C. R. Calvert, E. Hernandez-Echeagaray, O. K. Nguyen, E. Jocoy, L. J. Christian, M. A. Ariano, and M. S. Levine (2003)
J. Neurosci. 23, 961-969
   Abstract »    Full Text »    PDF »
Polyglutamine fibrillogenesis: The pathway unfolds.
C. A. Ross, M. A. Poirier, E. E. Wanker, and M. Amzel (2003)
PNAS 100, 1-3
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Provision of Brain-Derived Neurotrophic Factor via Anterograde Transport from the Eye Preserves the Physiological Responses of Axotomized Geniculate Neurons.
M. Caleo, P. Medini, C. S. von Bartheld, and L. Maffei (2003)
J. Neurosci. 23, 287-296
   Abstract »    Full Text »    PDF »
Calcium-dependent Cleavage of Endogenous Wild-type Huntingtin in Primary Cortical Neurons.
D. Goffredo, D. Rigamonti, M. Tartari, A. De Micheli, C. Verderio, M. Matteoli, C. Zuccato, and E. Cattaneo (2002)
J. Biol. Chem. 277, 39594-39598
   Abstract »    Full Text »    PDF »
Identification of a presymptomatic molecular phenotype in Hdh CAG knock-in mice.
E. Fossale, V. C. Wheeler, V. Vrbanac, L.-A. Lebel, A. Teed, J. S. Mysore, J. F. Gusella, M. E. MacDonald, and F. Persichetti (2002)
Hum. Mol. Genet. 11, 2233-2241
   Abstract »    Full Text »    PDF »
Caspase Cleavage of Mutant Huntingtin Precedes Neurodegeneration in Huntington's Disease.
C. L. Wellington, L. M. Ellerby, C.-A. Gutekunst, D. Rogers, S. Warby, R. K. Graham, O. Loubser, J. van Raamsdonk, R. Singaraja, Y.-Z. Yang, et al. (2002)
J. Neurosci. 22, 7862-7872
   Abstract »    Full Text »    PDF »
Dysregulation of gene expression in the R6/2 model of polyglutamine disease: parallel changes in muscle and brain.
R. Luthi-Carter, S. A. Hanson, A. D. Strand, D. A. Bergstrom, W. Chun, N. L. Peters, A. M. Woods, E. Y. Chan, C. Kooperberg, D. Krainc, et al. (2002)
Hum. Mol. Genet. 11, 1911-1926
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Increased huntingtin protein length reduces the number of polyglutamine-induced gene expression changes in mouse models of Huntington's disease.
E. Y.W. Chan, R. Luthi-Carter, A. Strand, S. M. Solano, S. A. Hanson, M. M. DeJohn, C. Kooperberg, K. O. Chase, M. DiFiglia, A. B. Young, et al. (2002)
Hum. Mol. Genet. 11, 1939-1951
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Early transcriptional profiles in huntingtin-inducible striatal cells by microarray analyses.
S. Sipione, D. Rigamonti, M. Valenza, C. Zuccato, L. Conti, J. Pritchard, C. Kooperberg, J. M. Olson, and E. Cattaneo (2002)
Hum. Mol. Genet. 11, 1953-1965
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Altered transcriptional regulation in cells expressing the expanded polyglutamine androgen receptor.
A. P. Lieberman, G. Harmison, A. D. Strand, J. M. Olson, and K. H. Fischbeck (2002)
Hum. Mol. Genet. 11, 1967-1976
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Tauroursodeoxycholic acid, a bile acid, is neuroprotective in a transgenic animal model of Huntington's disease.
C. D. Keene, C. M. P. Rodrigues, T. Eich, M. S. Chhabra, C. J. Steer, and W. C. Low (2002)
PNAS 99, 10671-10676
   Abstract »    Full Text »    PDF »
Modification of Brain Aging and Neurodegenerative Disorders by Genes, Diet, and Behavior.
M. P. Mattson, S. L. Chan, and W. Duan (2002)
Physiol Rev 82, 637-672
   Abstract »    Full Text »    PDF »
Calpain Activation in Huntington's Disease.
J. Gafni and L. M. Ellerby (2002)
J. Neurosci. 22, 4842-4849
   Abstract »    Full Text »    PDF »
Polyglutamine-Expanded Ataxin-7 Promotes Non-Cell-Autonomous Purkinje Cell Degeneration and Displays Proteolytic Cleavage in Ataxic Transgenic Mice.
G. A. Garden, R. T. Libby, Y.-H. Fu, Y. Kinoshita, J. Huang, D. E. Possin, A. C. Smith, R. A. Martinez, G. C. Fine, S. K. Grote, et al. (2002)
J. Neurosci. 22, 4897-4905
   Abstract »    Full Text »    PDF »
Alterations in the Mouse and Human Proteome Caused by Huntington's Disease.
C. Zabel, D. C. Chamrad, J. Priller, B. Woodman, H. E. Meyer, G. P. Bates, and J. Klose (2002)
Mol. Cell. Proteomics 1, 366-375
   Abstract »    Full Text »    PDF »
The Mitochondrial Toxin 3-Nitropropionic Acid Induces Striatal Neurodegeneration via a c-Jun N-Terminal Kinase/c-Jun Module.
M. Garcia, P. Vanhoutte, C. Pages, M.-J. Besson, E. Brouillet, and J. Caboche (2002)
J. Neurosci. 22, 2174-2184
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Early phenotypes that presage late-onset neurodegenerative disease allow testing of modifiers in Hdh CAG knock-in mice.
V. C. Wheeler, C.-A. Gutekunst, V. Vrbanac, L.-A. Lebel, G. Schilling, S. Hersch, R. M. Friedlander, J. F. Gusella, J.-P. Vonsattel, D. R. Borchelt, et al. (2002)
Hum. Mol. Genet. 11, 633-640
   Abstract »    Full Text »    PDF »


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