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 Ca(2+)/
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.