PMID- 18086127 OWN - NLM STAT- MEDLINE DCOM- 20080506 LR - 20211020 IS - 1471-4159 (Electronic) IS - 0022-3042 (Print) IS - 0022-3042 (Linking) VI - 105 IP - 2 DP - 2008 Apr TI - Brain-derived neurotrophic factor over-expression in the forebrain ameliorates Huntington's disease phenotypes in mice. PG - 369-79 AB - 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. FAU - Gharami, Kusumika AU - Gharami K AD - Department of Pharmacology, Georgetown University School of Medicine, Washington, District of Columbia 20057, USA. FAU - Xie, Yuxiang AU - Xie Y FAU - An, Juan Ji AU - An JJ FAU - Tonegawa, Susumu AU - Tonegawa S FAU - Xu, Baoji AU - Xu B LA - eng GR - R01 NS050596-03/NS/NINDS NIH HHS/United States GR - R01 NS050596/NS/NINDS NIH HHS/United States GR - R01 NS050596-02/NS/NINDS NIH HHS/United States GR - R01 NS050596-01A1S1/NS/NINDS NIH HHS/United States GR - NS050596/NS/NINDS NIH HHS/United States GR - R56 NS050596/NS/NINDS NIH HHS/United States GR - R01 NS050596-01A1/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20071212 PL - England TA - J Neurochem JT - Journal of neurochemistry JID - 2985190R RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Dopamine and cAMP-Regulated Phosphoprotein 32) RN - 0 (Enkephalins) RN - 0 (Htt protein, mouse) RN - 0 (Huntingtin Protein) RN - 0 (Nerve Tissue Proteins) RN - 0 (Nuclear Proteins) RN - 0 (Ppp1r1b protein, mouse) SB - IM MH - Animals MH - Brain-Derived Neurotrophic Factor/genetics/*metabolism MH - Disease Models, Animal MH - Dopamine and cAMP-Regulated Phosphoprotein 32/genetics/metabolism MH - Enkephalins/genetics/metabolism MH - Gene Expression Regulation/genetics/*physiology MH - Huntingtin Protein MH - Huntington Disease/genetics/*pathology MH - Mice MH - Mice, Inbred C57BL MH - Mice, Transgenic MH - Nerve Tissue Proteins/genetics/metabolism MH - Nuclear Proteins/genetics/metabolism MH - *Phenotype MH - Prosencephalon/*metabolism PMC - PMC2377033 MID - NIHMS45343 EDAT- 2007/12/19 09:00 MHDA- 2008/05/07 09:00 PMCR- 2009/04/01 CRDT- 2007/12/19 09:00 PHST- 2007/12/19 09:00 [pubmed] PHST- 2008/05/07 09:00 [medline] PHST- 2007/12/19 09:00 [entrez] PHST- 2009/04/01 00:00 [pmc-release] AID - JNC5137 [pii] AID - 10.1111/j.1471-4159.2007.05137.x [doi] PST - ppublish SO - J Neurochem. 2008 Apr;105(2):369-79. doi: 10.1111/j.1471-4159.2007.05137.x. Epub 2007 Dec 12.