Roles of BDNF in Striatal Neurons and Relevance to Huntington's Disease

神经营养因子调节中枢神经系统中多种神经元的功能和存活 它们的缺陷可能在神经退行性疾病的进展中发挥关键作用。这 应用目的：探讨脑源性神经营养因子(BDNF)在糖尿病发病机制中的作用 亨廷顿氏病(HD)，纹状体中的棘神经元选择性丢失。HD是由以下原因引起的 CAG在编码亨廷顿蛋白的HD基因中重复扩增。纹状体神经元表达脑源性神经营养因子 受体TrkB，但不表达主要通过顺行转运到达纹状体的BDNF 来自大脑皮层神经元。已有研究表明，HD突变通过以下方式降低纹状体中BDNF的水平 抑制脑源性神经营养因子基因转录和顺行转运。这个项目将检验这样一个假设： 通过检测TrkB信号通路的作用，发现纹状体BDNF供应减少与HD的发病机制有关 在纹状体神经元的正常功能和存活中，通过确定TrkB的减少是否 信号使纹状体神经元对突变的亨廷顿蛋白的毒性作用敏感，并通过测试 增加纹状体BDNF水平可延缓HD的发生。TrkB基因在小鼠中的突变体 具体删除的纹状体将被用来检查TrkB信号是否需要 纹状体神经元的正常功能和存活。一个TrkB亚型等位基因将用于产生HD 表达TrkB的转基因小鼠的数量是正常值的100%或25%。这些突变的小鼠将会是 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，脑源性神经营养因子在皮质神经元中过度表达的可能性延缓了 HD的发病将在HD和BDNF双转基因小鼠中进行研究。这项研究可能会导致 BDNF-TrkB通路的发现有望成为设计有效治疗方案的靶点 亨廷顿氏病。

Neurotrophins regulate function and 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 medium spiny neurons are selectively lost. HD is causedby 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. It has been shown that the HD mutation reduces the BDNF level in the striatum by inhibiting BDNF gene transcription and anterograde transport. This project will test the hypothesis that the reduced striatal BDNF supply is relevant to the pathogenesis of HD by examining the role of TrkB signaling in the normal function and survival of striatal neurons, by determining whether a reduction in TrkB signaling sensitizes striatal neurons to the toxic effect of mutant huntingtin, and by testing whether increasing the striatal BDNF level delays the onset of HD. Mouse mutants in which the trkB gene is specifically deleted in the striatum will be used to examine whether TrkB signaling is required for the normal function and survival of striatal neurons. One trkB hypomorphic allele will be used to produce HD transgenic mice that express TrkB at 100% or 25% of the normal amount. 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.