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

2001; American Association for the Advancement of Science; Volume: 293; Issue: 5529 Linguagem: Inglês

10.1126/science.1059581

1095-9203

Chiara Zuccato, Andrea Ciammola, Dorotea Rigamonti, Blair R. Leavitt, Donato Goffredo, Luciano Conti, Marcy E. MacDonald, Robert M. Friedlander, Vincenzo Silani, Michael R. Hayden, Tõnis Timmusk, Simonetta Sipione, Elena Cattaneo,

Muscle Physiology and Disorders

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.