NEUROPATHOLOGY AND PATHOGENESIS OF HUNTINGTONS DISEASE

我们之前发现，基于免疫组织化学研究， 死后的人脑材料，即某些类型的纹状体投射 在亨廷顿病(HD)中，神经元比其他人更脆弱， 易受攻击的类型在中期大量消失 成人起病阶段。为了更好地描述这种差异 纹状体投射神经元的丢失，我们建议用免疫组织化学 尸检脑组织标本的技术：1)检查脑组织的形态 成人起病早期和晚期HD类型中的丢失 我们已经研究过的投射神经元；2)0检查丢失的模式 在成人HD的所有阶段进行某些额外类型的纹状体投射 神经元和3)检查幼年起病HD的早期和晚期 探讨在这种形式的HD中纹状体之间的丢失的可能性 投射神经元是不可区分的(这一点从我们的初步研究中可以看出 数据和这种形式的HD的临床特征)。图像分析将是 用来量化损失的程度，与每种情况的正常程度相比较 项目体系。 这些关于HD差异纹状体投射神经元易损性的数据 将为大鼠的两条研究路线提供重要信息，两者都 其中涉及到兴奋性毒性在介导 HD患者纹状体细胞死亡。在第一线的研究中，我们将确定 纹状体投射神经元和中间神经元是否较少 易患HD的人具有更大的细胞内缓冲能力 钙(通过其小白蛋白或钙结合蛋白的含量)和 从而可以防止由 参加兴奋性毒性事件的高钙内流。在第二行 我们将检查体内纹状体神经元的暴露(通过 纹状体内注射的方法)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的作用， 喹啉酸(QA)，产生纹状体的差异死亡模式 HD中可见投射神经元和中间神经元。如果是这样，结果是 支持HD中细胞死亡可能是由 NMDA受体介导的神经毒性。 拟议的研究将有助于阐明这些症状的神经基础。 在HD的每个阶段进行观察并阐明其发病机制 潜在的HD，特别是关于NMDA受体介导的假设 兴奋性可能低于HD。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作用 携带者，以及其他涉及兴奋性毒素介导的疾病 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.