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BDNF overexpression in the forebrain rescues Huntington's disease phenotypes in YAC128 mice

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Overview

authors

  • Xie, Y.
  • Hayden, M. R.
  • Xu, Baoji

publication date

  • November 2010

journal

  • Journal of Neuroscience  Journal

abstract

  • Huntington's disease (HD) is caused by an expansion of the polyglutamine tract at the N terminus of huntingtin. This mutation reduces levels of BDNF in the striatum, likely by inhibiting cortical Bdnf gene expression and anterograde transport of BDNF from the cerebral cortex to the striatum. Substantial evidence suggests that this reduction of striatal BDNF plays a crucial role in HD pathogenesis. Here we report that overexpression of BDNF in the forebrain rescues many disease phenotypes in YAC128 mice that express a full-length human huntingtin mutant with a 128-glutamine tract. The Bdnf transgene, under the control of the promoter for ? subunit of Ca(2+)/calmodulin-dependent protein kinase II, greatly increased BDNF levels in the cerebral cortex and striatum. BDNF overexpression in YAC128 mice prevented loss and atrophy of striatal neurons and motor dysfunction, normalized expression of the striatal dopamine receptor D2 and enkephalin, and improved procedural learning. Furthermore, quantitative analyses of Golgi-impregnated neurons revealed a decreased spine density and abnormal spine morphology in striatal neurons of YAC128 mice, which was also reversed by increasing BDNF levels in the striatum. These results demonstrate that reduced striatal BDNF plays a crucial role in the HD pathogenesis and suggest that attempts to restore striatal BDNF level may have therapeutic effects to the disease.
  • Huntington's disease (HD) is caused by an expansion of the polyglutamine tract at the N terminus of huntingtin. This mutation reduces levels of BDNF in the striatum, likely by inhibiting cortical Bdnf gene expression and anterograde transport of BDNF from the cerebral cortex to the striatum. Substantial evidence suggests that this reduction of striatal BDNF plays a crucial role in HD pathogenesis. Here we report that overexpression of BDNF in the forebrain rescues many disease phenotypes in YAC128 mice that express a full-length human huntingtin mutant with a 128-glutamine tract. The Bdnf transgene, under the control of the promoter for α subunit of Ca(2+)/calmodulin-dependent protein kinase II, greatly increased BDNF levels in the cerebral cortex and striatum. BDNF overexpression in YAC128 mice prevented loss and atrophy of striatal neurons and motor dysfunction, normalized expression of the striatal dopamine receptor D2 and enkephalin, and improved procedural learning. Furthermore, quantitative analyses of Golgi-impregnated neurons revealed a decreased spine density and abnormal spine morphology in striatal neurons of YAC128 mice, which was also reversed by increasing BDNF levels in the striatum. These results demonstrate that reduced striatal BDNF plays a crucial role in the HD pathogenesis and suggest that attempts to restore striatal BDNF level may have therapeutic effects to the disease.

subject areas

  • Animals
  • Brain-Derived Neurotrophic Factor
  • Corpus Striatum
  • Disease Models, Animal
  • Gene Expression Regulation
  • Genetic Therapy
  • Humans
  • Huntington Disease
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mutation
  • Nerve Tissue Proteins
  • Neurons
  • Nuclear Proteins
  • Peptides
  • Phenotype
  • Promoter Regions, Genetic
  • Prosencephalon
  • Recovery of Function
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Identity

PubMed Central ID

  • PMC2989389

International Standard Serial Number (ISSN)

  • 0270-6474

Digital Object Identifier (DOI)

  • 10.1523/jneurosci.1637-10.2010

PubMed ID

  • 21048129
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Additional Document Info

start page

  • 14708

end page

  • 14718

volume

  • 30

issue

  • 44

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