Neuropathology and Pathogenesis of Huntington's Disease

亨廷顿氏病（HD）是一种遗传性神经退行性疾病， 由于大脑皮层早期发生功能障碍和进行性 由于基底神经节纹状体投射神经元的稳定丧失而导致的运动控制下降。而 突变的亨廷顿蛋白（Htt）是HD发病机制的基础， 细胞功能，突变体Htt引起HD皮质和纹状体病理的手段 仍然不确定。几条证据表明Htt突变导致BDNF减少， （脑源性神经营养因子）的生产和运输的皮质纹状体神经元，导致 剥夺纹状体神经元的这种重要的营养因子，这可能是主要的手段， HD破坏纹状体投射神经元。然而，尚不清楚BDNF引起的纹状体病理是否 剥夺是真正的HD样，目前尚不清楚如果HD突变启动纹状体损伤过程， 由促存活BDNF信号传导的缺陷介导。本建议旨在解决这两个问题 问题，以更坚定地建立，如果BDNF剥夺发挥了重要作用，在纹状体损伤过程中， HD.如果证实与此有关，那么BDNF替代疗法将是一种可行的方法， HD中的纹状体损伤，例如通过纹状体植入工程化以产生BDNF的干细胞。 此外，如果我们的研究确定大脑皮层是突变的主要部位， 导致间接纹状体损伤，我们的研究结果将指导寻求减少突变蛋白的治疗， 表达到靶皮质。将开展四个方面的研究，每个方面解决一个关键问题， 假设纹状体剥夺皮质产生的BDNF是HD纹状体损伤的基础。目标1。 BDNF在皮质纹状体神经元的定位及其受体trkB在纹状体投射神经元的定位是否与脑梗死相关性有关？ 正常动物与HD纹状体投射神经元之间的差异脆弱性一致？目的 2.纹状体投射神经元对BDNF剥夺的脆弱性是否与它们的分化一致？ HD中的漏洞？目标3。什么样的细胞内信号通路介导BDNF的有害作用 剥夺纹状体投射神经元目标4。HD突变会对纹状体投射造成损伤吗 神经元通过BDNF剥夺所使用的细胞内信号通路？研究将采用 HD和BDNF表达的皮质特异性敲除的突变小鼠模型，以及体外方法。

Huntington¿s disease (HD) is a hereditary neurodegenerative disorder that results in a progressive decline in cognitive ability due to an early occurring dysfunction in cerebral cortex and a progressive decline in motor control due to the steady loss of striatal projection neurons from the basal ganglia. While the mutated huntingtin protein (Htt) that underlies HD pathogenesis appears to interfere with a wide array of cellular functions, the means by which mutant Htt brings about the cortical and striatal pathology of HD remains uncertain. Several lines of evidence suggest that the Htt mutation causes a reduction in BDNF (brain-derived neurotrophic factor) production and transport by corticostriatal neurons, resulting in deprivation of striatal neurons of this vital trophic factor, and that this may be the major means by which HD destroys striatal projection neurons. It is unknown, however, if the striatal pathology caused by BDNF deprivation is truly HD-like, and it is unknown if the HD mutation initiates a striatal injury process that is mediated by a deficit in pro-survival BDNF signaling. The present proposal seeks to address these two issues to more firmly establish if BDNF deprivation plays a significant role in the striatal injury process in HD. If shown to be implicated, BDNF replacement therapy would then be a viable approach for combating striatal injury in HD, for example by means of striatal implant of stem cells engineered to produce BDNF. Moreover, if the cerebral cortex is identified by our studies as the primary site at which the mutation acts to bring about indirect striatal injury, our findings would guide therapies seeking to reduce mutant protein expression to target cortex. Four lines of study will be carried out, each to address a key question related to the hypothesis that striatal deprivation of cortically produced BDNF underlies striatal injury in HD. Aim 1. Are the localization of BDNF in corticostriatal neurons and its receptor trkB in striatal projection neurons in normal animals consistent with the differential vulnerability among striatal projection neurons in HD? Aim 2. Is the vulnerability of striatal projection neurons to BDNF deprivation consistent with their differential vulnerability in HD? Aim 3. What intracellular signaling pathways mediate the deleterious effects of BDNF deprivation on striatal projection neurons? Aim 4. Does the HD mutation cause injury to striatal projection neurons via the intracellular signaling pathways used by BDNF deprivation? The studies will employ mutant mouse models of HD and cortex-specific knockout of BDNF expression, and in vitro approaches.