NEUROPATHOLOGY AND PATHOGENESIS OF HUNTINGTONS DISEASE

我们以前发现，基于免疫组织化学研究， 死后的人脑材料，某些类型的纹状体投射 在亨廷顿病（HD）中，神经元比其他神经元更脆弱， 脆弱的种类在中期大量减少， 成人HD发病阶段。 为了更好地描述微分 纹状体投射神经元的损失，我们建议使用免疫组织化学 技术对死后大脑标本：1）检查模式 在成人发病HD的早期和晚期， 我们已经研究过的投射神经元; 2）检查丢失的模式 在成人HD的所有阶段，对于某些额外类型的纹状体投射， 神经元和3）检查青少年发病HD的早期和晚期阶段， 探索这种形式的HD中纹状体之间的丢失的可能性， 投射神经元是非微分的（这是我们的初步研究所暗示的）。 数据和这种形式的HD的临床特征）。 图像分析将 用于量化与正常值相比的损失程度， 项目体系 这些数据差异纹状体投射神经元脆弱性在HD 将为大鼠的两条研究线提供重要信息， 其中涉及兴奋性毒性在介导 HD中的纹状体细胞死亡。 在研究的第一线，我们将确定 是否纹状体投射神经元和中间神经元， HD易感者具有更大的细胞内缓冲能力 钙（通过其小清蛋白或钙结合蛋白的含量）， 从而可以防止有害的级联事件， 伴随兴奋性毒性事件的高钙流入。 第二行中 的工作，我们将研究是否暴露纹状体神经元在体内（通过 纹状体内注射）或体外（通过培养的 纹状体神经元）对内源性NMDA受体特异性兴奋性毒素， 喹啉酸（QA），产生纹状体细胞的差异性死亡模式， 在HD中观察到投射神经元和中间神经元。 如果是这样， 支持HD中的细胞死亡可能是由 NMDA受体介导的兴奋毒性。 拟议中的研究将有助于澄清症状的神经基础 观察HD的各个阶段，并阐明发病机制 潜在的HD，特别是在假设NMDA受体介导的 兴奋毒性可能是HD的基础。 从这些不同的信息中获得的信息 研究可能对HD基因具有治疗或预防意义 携带者以及涉及兴奋性毒素介导的其它病症 神经元变性

We have previously found, based on immunohistochemical studies of postmortem human brain material, that some types of striatal projection neurons are more vulnerable than others in Huntington's disease (HD), with the vulnerable types being lost in greater abundance during the middle stages of adult onset HD. In order to better characterize the differential loss of striatal projection neurons, we propose to use immunohistochemical techniques on postmortem brain specimens to: 1) examine the patterns of loss in the early and late stages of adult onset HD among the types of projection neurons we have already studied; 2)0 examine the pattern of loss at all stages of adult HD for some additional types of striatal projection neurons and 3) examine the early and late stages of juvenile onset HD to explore the possibility that in this form of HD the loss among striatal projection neurons is nondifferential (which is implied by our preliminary data and the clinical features of this form of HD). Image analysis will be used to quantify the extent of loss in comparison to normals for each project system. These data on differential striatal projection neuron vulnerability in HD will provide important information for two lines of studies in rats, both of which relate to the possible role of excitotoxicity in mediating striatal cell death in HD. In the first line of study, we will determine whether striatal projection neurons and interneurons that are less susceptible in HD possess a greater capacity for buffering intracellular calcium (by means of their content of either parvalbumin or calbindin) and can thereby prevent the deleterious cascade of events that ensues from the high calcium influxes that attend an excitotoxic event. In the second line of work we will examine whether exposure of striatal neurons in vivo (by means of intrastriatal injections) or in vitro (by incubation of cultured striatal neurons) to the endogenous NMDA-receptor specific excitotoxin, quinolinic acid (QA), yields the pattern of differential death of striatal projection neurons and interneurons observed in HD. If so, the results would support the possibility that cell death in HD might be mediated by NMDA receptor mediated exictotoxicity. The proposed studies will help clarify the neural bases of the symptoms observed at each stage of HD and shed light on the pathogenetic mechanisms underlying HD, particularly on the hypothesis that NMDA-receptor mediated excitoxicity might underly HD. The information gained from these various studies could have therapeutic or prophylactic implications for HD gene carriers, as well as for other disorders involving excitotoxin-mediated neuronal degeneration.