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

描述（由申请人提供）：纹状体是基底神经节的最大组成部分，其变性是亨廷顿氏病（HD）相关运动功能障碍的原因，亨廷顿氏病是一种主要遗传的神经退行性疾病，由亨廷顿蛋白（htt） n端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（MSNs），其余为中间神经元。msn分为两类：在间接途径中表达多巴胺受体D2 （DRD2）的msn和在直接途径中表达多巴胺受体D1a （DRD1a）的msn。研究表明，msn生于外侧神经节隆起（LGE）；然而，对于msn的进一步发展是如何受到调控的，在很大程度上仍然未知。目前尚不清楚的是，普遍表达的htt突变如何导致纹状体中选择性和严重的神经元丢失，以及皮层中较少程度的神经元丢失，以及为什么DRD2 msn是HD患者纹状体中受影响最大的细胞。我们假设顺行转运的脑源性神经营养因子（BDNF）和神经营养因子-3 （NT3）控制新生儿mscs的存活和树突化。我们进一步假设树突中突变htt的局部合成在HD发病机制中起关键作用，并且msn中TrkB （BDNF受体）的差异表达有助于HD的选择性变性。这些假设是基于我们之前研究的有力证据。这个研究项目有四个具体目标。特异性目的1是研究从黑质纹状体多巴胺能神经元顺行转运的BDNF和NT3是否通过删除多巴胺能神经元中的BDNF或NT3基因来支持新生mnsn的存活。特异性目的2是通过培养纹状体神经元和DRD2表达细胞中TrkB基因缺失的突变小鼠，确定BDNF是否需要DRD2 msn树突化的发展。特异性目的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，以及突变亨廷顿蛋白的树突合成是否与培养神经元的HD发病有关。特异性目的4是通过在成年野生型和HD小鼠的DRD2表达细胞中删除TrkB基因，研究DRD2 msn中TrkB的优先表达是否有助于HD的选择性变性。这项研究的结果将为纹状体发育的调控和HD的发病机制提供新的见解。

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. PUBLIC HEALTH RELEVANCE: The striatum is the largest component of the basal ganglia and is associated with several neurological disorders, including Huntington's disease (HD). Findings from this proposed research will provide important information as to HD pathogenesis and cell replacement therapy for striatum-based diseases.