Roles of BDNF in Striatal Neurons and Relevance to HD

描述（由申请人提供）：神经营养因子促进中枢神经系统中许多神经元群体的存活，其缺陷可能在神经退行性疾病的进展中起关键作用。本申请旨在研究脑源性神经营养因子（BDNF）在亨廷顿病（HD）发病机制中的作用，其中纹状体神经元选择性丢失。HD是由编码亨廷顿蛋白的HD基因中CAG重复序列的扩增引起的。纹状体神经元表达BDNF受体TrkB，但不表达BDNF，BDNF主要通过从皮层神经元的顺行运输到达纹状体。野生型亨廷顿蛋白诱导，但突变亨廷顿蛋白抑制，脑源性神经营养因子基因转录在皮层神经元。此外，突变的亨廷顿蛋白已被证明可以阻断苍蝇和鱿鱼的轴突运输。本项目将检验以下假设：TrkB信号传导是纹状体神经元存活所必需的，HD基因突变通过抑制BDNF的表达和顺行转运减少TrkB信号传导，这沿着突变亨廷顿蛋白的其他有害作用，导致纹状体神经元变性。其中在纹状体中特异性缺失trkB基因的小鼠突变体将用于检查TrkB信号传导是否是纹状体神经元存活所需的。将在HD转基因小鼠模型中检查突变亨廷顿蛋白对BDNF表达和顺行转运的影响。将使用两个trkB突变等位基因来产生分别以正常量的100%、50%、24%或12%表达TrkB的HD转基因小鼠。然后，这些突变小鼠将用于确定表达突变亨廷顿蛋白的纹状体神经元是否更依赖于神经营养保护。最后，在HD和BDNF双转基因小鼠中研究皮质神经元中BDNF过表达延迟HD发作的可能性。这项研究可能会发现BDNF-TrkB通路作为设计亨廷顿病有效治疗方法的一个有希望的靶点。

DESCRIPTION (provided by applicant): Neurotrophins promote survival of many populations of neurons in the central nervous system and their deficiencies may play a pivotal role in the progression of neurodegenerative diseases. This application aims to examine the role of brain-derived neurotrophic factor (BDNF) in the pathogenesis of Huntington's disease (HD) in which striatal neurons are selectively lost. HD is caused by expansion of CAG repeats in the HD gene that encodes huntingtin. Striatal neurons express the BDNF receptor, TrkB, but do not express BDNF which mainly arrives at the striatum by anterograde transport from cortical neurons. Wild-type huntingtin induces, but mutant huntingtin inhibits, BDNF gene transcription in cortical neurons. Furthermore, mutant huntingtin has been shown to block axonal transport in fly and squid. This project will test the hypothesis that TrkB signaling is required for survival of striatal neurons and that the mutation in the HD gene reduces TrkB signaling by inhibiting expression and anterograde transport of BDNF, which, along with other deleterious effects of mutant huntingtin, leads to degeneration of striatal neurons. Mouse mutants in which the trkB gene is specifically deleted in the striatum will be used to examine whether TrkB signaling is required for survival of striatal neurons. The effect of mutant huntingtin on expression and anterograde transport of BDNF will be examined in HD transgenic mouse models. Two trkB mutant alleles will be used to produce HD transgenic mice that express TrkB at 100%, 50%, 24% or 12% of the normal amount, respectively. These mutant mice will then be used to determine whether striatal neurons expressing mutant huntingtin are more dependent on neurotrophic protection. Finally, the possibility that BDNF overexpression in cortical neurons delays the onset of HD will be investigated in HD and BDNF double transgenic mice. This research may lead to discovery of the BDNF-TrkB pathway as a promising target for designing effective treatments of Huntington's disease.