Loss of huntingtin-mediated BDNF gene transcription in Huntington's disease.

Abstract	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.
Authors	C Zuccato, A Ciammola, D Rigamonti, B R Leavitt, D Goffredo, L Conti, M E MacDonald, R M Friedlander, V Silani, M R Hayden, T Timmusk, S Sipione, E Cattaneo
Journal	Science (New York, N.Y.) (Science) Vol. 293 Issue 5529 Pg. 493-8 (Jul 20 2001) ISSN: 0036-8075 [Print] United States
PMID	11408619 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Brain-Derived Neurotrophic Factor HTT protein, human Htt protein, mouse Huntingtin Protein Nerve Growth Factors Nerve Tissue Proteins Nuclear Proteins
Topics	3T3 Cells Animals Apoptosis Brain-Derived Neurotrophic Factor (biosynthesis, genetics, metabolism) Cell Survival Cells, Cultured Cerebral Cortex (cytology, metabolism) Corpus Striatum (cytology, metabolism, pathology) Exons Hippocampus (cytology, metabolism, pathology) Humans Huntingtin Protein Huntington Disease (genetics, metabolism, pathology) Mice Mice, Transgenic Mutation Nerve Degeneration Nerve Growth Factors (genetics, metabolism) Nerve Tissue Proteins (genetics, physiology) Neurons (metabolism, pathology) Nuclear Proteins (genetics, physiology) Promoter Regions, Genetic Transcription, Genetic Transfection

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