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

Science. 2001 Jul 20;293(5529):493-8. doi: 10.1126/science.1059581. Epub 2001 Jun 14.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Animals
  • Apoptosis
  • Brain-Derived Neurotrophic Factor / biosynthesis
  • Brain-Derived Neurotrophic Factor / genetics*
  • Brain-Derived Neurotrophic Factor / metabolism
  • Cell Survival
  • Cells, Cultured
  • Cerebral Cortex / cytology
  • Cerebral Cortex / metabolism*
  • Corpus Striatum / cytology
  • Corpus Striatum / metabolism*
  • Corpus Striatum / pathology
  • Exons
  • Hippocampus / cytology
  • Hippocampus / metabolism
  • Hippocampus / pathology
  • Humans
  • Huntingtin Protein
  • Huntington Disease / genetics*
  • Huntington Disease / metabolism
  • Huntington Disease / pathology
  • Mice
  • Mice, Transgenic
  • Mutation
  • Nerve Degeneration
  • Nerve Growth Factors / genetics
  • Nerve Growth Factors / metabolism
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / physiology*
  • Neurons / metabolism*
  • Neurons / pathology
  • Nuclear Proteins / genetics
  • Nuclear Proteins / physiology*
  • Promoter Regions, Genetic
  • Transcription, Genetic
  • Transfection

Substances

  • Brain-Derived Neurotrophic Factor
  • HTT protein, human
  • Htt protein, mouse
  • Huntingtin Protein
  • Nerve Growth Factors
  • Nerve Tissue Proteins
  • Nuclear Proteins