Neuropathology and Pathogenesis of Huntington's Disease

亨廷顿S病(HD)是一种遗传性神经退行性疾病，可导致进行性 由于大脑皮质功能障碍而导致的认知能力下降和进行性 由于基底节纹状体投射神经元的稳定丢失，运动控制能力下降。而当 HD发病机制背后的突变亨廷顿蛋白(Htt)似乎干扰了广泛的序列 细胞功能，突变的Htt导致HD的皮质和纹状体病理的方式 目前仍不确定。多条证据表明，htt突变导致BDNF减少 (脑源性神经营养因子)由皮质纹状体神经元产生和运输，导致 剥夺纹状体神经元这种重要的营养因子，这可能是 HD会破坏纹状体投射神经元。然而，目前尚不清楚脑源性神经营养因子引起的纹状体病理 剥夺是真正类似HD的，目前尚不清楚HD突变是否会启动纹状体损伤过程 由支持生存的脑源性神经营养因子信号的缺陷所介导。目前的建议旨在解决这两个问题 更确切地确定剥夺BDNF是否在纹状体损伤过程中起重要作用的问题 高清。如果被证实有牵连，BDNF替代疗法将是一种可行的抗击 HD中的纹状体损伤，例如通过纹状体植入经改造产生BDNF的干细胞。 此外，如果我们的研究确定大脑皮层是突变作用的主要部位 导致间接纹状体损伤，我们的发现将指导寻求减少突变蛋白的治疗 表达到靶区皮质。将进行四条研究路线，每条路线都要解决与以下方面有关的一个关键问题 假设纹状体剥夺皮质产生的脑源性神经营养因子是HD纹状体损伤的基础。目标1。 脑源性神经营养因子在皮质纹状体神经元及其受体TrkB在纹状体投射神经元中的定位 正常动物与HD纹状体投射神经元之间的易损性差异一致？目标 2.纹状体投射神经元对脑源性神经营养因子剥夺的易感性是否与它们的差异一致 高清中的漏洞？目的3.什么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？目的4.HD突变是否对纹状体投射造成损伤 脑源性神经营养因子剥夺所使用的细胞内信号通路？这些研究将采用 HD和皮层特异性敲除BDNF表达的突变小鼠模型，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.