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

描述（由申请人提供）：神经营养因子调节中枢神经系统中许多神经元的功能和存活，它们的缺乏可能在神经退行性疾病的进展中起关键作用。本应用程序旨在研究脑源性神经营养因子（BDNF）在亨廷顿氏病（HD）发病机制中的作用，其中纹状体中棘神经元选择性丢失。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主要通过皮层神经元的顺行运输到达纹状体。研究表明，HD突变通过抑制BDNF基因转录和顺行转运来降低纹状体中的BDNF水平。该项目将通过检测TrkB信号在纹状体神经元正常功能和存活中的作用，通过确定TrkB信号的减少是否使纹状体神经元对突变亨廷顿蛋白的毒性作用敏感，以及通过测试纹状体BDNF水平的增加是否会延迟HD的发病，来验证纹状体BDNF供应减少与HD发病机制相关的假设。trkB基因在纹状体中被特异性删除的小鼠突变体将被用于检查trkB信号是否对纹状体神经元的正常功能和存活是必需的。一个trkB亚型等位基因将被用于产生表达正常trkB量的100%或25%的HD转基因小鼠。这些突变小鼠将被用来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，我们将在HD和BDNF双转基因小鼠中研究皮质神经元中BDNF过表达延缓HD发病的可能性。这项研究可能会发现BDNF-TrkB通路作为设计有效治疗亨廷顿病的有希望的靶点。

DESCRIPTION (provided by applicant): 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 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. 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.