Brain‐derived neurotrophic factor over‐expression in the forebrain ameliorates Huntington's disease phenotypes in mice

K Gharami, Y Xie, JJ An, S Tonegawa… - Journal of …, 2008 - Wiley Online Library
K Gharami, Y Xie, JJ An, S Tonegawa, B Xu
Journal of neurochemistry, 2008Wiley Online Library
Abstract Huntington's disease (HD), a dominantly inherited neurodegenerative disorder
characterized by relatively selective degeneration of striatal neurons, is caused by an
expanded polyglutamine tract of the huntingtin (htt) protein. The htt mutation reduces levels
of brain‐derived neurotrophic factor (BDNF) in the striatum, likely by inhibiting cortical BDNF
gene expression and anterograde transport of BDNF from cortex to striatum. However, roles
of the BDNF reduction in HD pathogenesis have not been established conclusively. We …
Abstract
Huntington’s disease (HD), a dominantly inherited neurodegenerative disorder characterized by relatively selective degeneration of striatal neurons, is caused by an expanded polyglutamine tract of the huntingtin (htt) protein. The htt mutation reduces levels of brain‐derived neurotrophic factor (BDNF) in the striatum, likely by inhibiting cortical BDNF gene expression and anterograde transport of BDNF from cortex to striatum. However, roles of the BDNF reduction in HD pathogenesis have not been established conclusively. We reasoned that increasing striatal BDNF through over‐expression would slow progression of the disease if BDNF reduction plays a pivotal role in HD pathogenesis. We employed a Bdnf transgene driven by the promoter for the alpha subunit of Ca2+/calmodulin‐dependent kinase II to over‐express BDNF in the forebrain of R6/1 mice which express a fragment of mutant htt with a 116‐glutamine tract. The Bdnf transgene increased BDNF levels and TrkB signaling activity in the striatum, ameliorated motor dysfunction, and reversed brain weight loss in R6/1 mice. Furthermore, it normalized DARPP‐32 expression of the 32 kDa dopamine and cAMP‐regulated phosphoprotein, increased the number of enkephalin‐containing boutons, and reduced formation of neuronal intranuclear inclusions in the striatum of R6/1 mice. These results demonstrate crucial roles of reduced striatal BDNF in HD pathogenesis and suggest potential therapeutic values of BDNF to HD.
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