Roles of BDNF in striatal neurons and relevance to Huntington's disease

描述(申请人提供)：纹状体是基底节的最大组成部分，其变性是与亨廷顿病(HD)相关的运动功能障碍的原因，亨廷顿病(HD)是一种主要遗传性神经退行性疾病，由亨廷顿蛋白(HTT)N端的聚谷氨酰胺束扩张引起。此外，它还与几种发育障碍有关。纹状体神经元绝大多数为中等大小的棘神经元，其余为中间神经元。MSN分为两类：在间接途径表达多巴胺受体D2(DRD2)的MSN和在直接途径表达多巴胺受体D1a(DRD1a)的MSN。研究表明，MSN出生于外侧神经节隆起(LGE)；然而，MSN的进一步发展是如何调控的，目前仍不清楚。目前还不清楚普遍表达的HTT的突变如何导致纹状体和皮质中选择性和严重的神经元丢失，以及为什么DRD2 MSN是HD患者纹状体内受影响最严重的细胞。我们推测，脑源性神经营养因子(BDNF)和神经营养因子-3(NT3)的顺向转运控制着新生MSN的存活和树突状分支。我们进一步假设树突状突变体HTT的局部合成在HD的发病机制中起关键作用，并且在MSN中TrkB(BDNF的受体)的差异表达有助于HD的选择性退变。这些假设是基于我们之前研究的强有力的证据。本研究项目有四个具体目标。具体目的1是研究黑质纹状体多巴胺能神经元顺行运输的BDNF和NT3是否通过缺失多巴胺能神经元中的BDNF或NT3基因来支持新生MSN的存活。具体目的2是通过使用培养的纹状体神经元和表达DRD2的细胞中TrkB基因缺失的突变小鼠，确定BDNF是否是DRD2 MSN树突状树枝形成所必需的。具体目的3是研究亨廷顿蛋白转录本是否被转运到树突进行局部翻译，以及突变的亨廷顿蛋白树突状合成是否与培养神经元的HD发病有关。特异目的4是检测DRD2 MSN中TrkB的优先表达是否通过删除成年野生型和HD小鼠DRD2表达细胞中的TrkB基因而导致HD选择性退变。这项拟议的研究结果将为纹状体发育的调节和HD的发病机制提供深入的见解。

DESCRIPTION (provided by applicant): The striatum is the largest component of the basal ganglia, and its degeneration is the cause for motor dysfunction associated with Huntington's disease (HD), a dominantly inherited neurodegenerative disorder caused by the expansion of a polyglutamine tract at the N-terminus of the huntingtin (htt) protein. In addition, it has been implicated in several developmental disorders. The vast majority of striatal neurons are medium- sized spiny neurons (MSNs) with the rest being interneurons. MSNs are divided into two populations: those expressing the dopamine receptor D2 (DRD2) in the indirect pathway and those expressing the dopamine receptor D1a (DRD1a) in the direct pathway. Studies have demonstrated that MSNs are born in the lateral ganglionic eminence (LGE); however, it remains largely unknown how the further development of MSNs is regulated. It also remains unclear how a mutation in the ubiquitously expressed htt causes selective and severe neuronal loss in the striatum and to a lesser extent in the cortex and why DRD2 MSNs are the most affected cells in the striata of HD patients. We hypothesize that anterogradely transported brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT3) control survival and dendritic arborization of newborn MSNs. We further hypothesize that local synthesis of mutant htt in dendrites plays a key role in the HD pathogenesis and that differential expression of TrkB (the receptor for BDNF) in MSNs contributes to selective degeneration in HD. These hypotheses are based on strong evidence from our previous studies. This research project has four specific aims. Specific Aim 1 is to investigate whether BDNF and NT3 transported anterogradely from nigrostriatal dopaminergic neurons support the survival of newborn MSNs by deleting the BDNF or Nt3 gene in dopaminergic neurons. Specific Aim 2 is to determine whether BDNF is required for the development of dendritic arborization of DRD2 MSNs by using cultured striatal neurons and mutant mice where the TrkB gene is deleted in DRD2-expressing cells. Specific Aim 3 is to investigate whether huntingtin transcripts are transported to dendrites for local translation and whether dendritic synthesis of mutant huntingtin contributes to the HD pathogenesis in cultured neurons. Specific Aim 4 is to examine whether the preferential TrkB expression in DRD2 MSNs contributes to selective degeneration in HD by deleting the TrkB gene in DRD2-expressing cells of adult wild-type and HD mice. Results from this proposed research will provide insights into the regulation of striatal development and the pathogenesis of HD.