Dissecting the Huntington's Disease mechanism

描述（研究者摘要）：亨廷顿病（HD）是一种主要的 遗传性神经退行性疾病，在美国影响1/10，000。 关于HD突变的知识，一种CAG扩增， 在亨廷顿蛋白中，促进了HD致病机制的阐明， 相关的多聚谷氨酰胺疾病。突变型亨廷顿舞蹈症致病触发因子 包括两个组分：赋予聚谷氨酰胺的新毒性性质， 和另一个350 kDa蛋白质的内在特征， 使得纹状体神经元特别脆弱通过插入HD CAG重复 进入小鼠的HD基因（Hdh），我们发现了异常的构象 截短聚集体之前的全长突变亨廷顿蛋白的性质 和神经元萎缩。纹状体神经元的特异性、优势性和谷氨酰胺 逐渐暗示这些事件在人类疾病的早期。我们有 Hdh失活和纹状体细胞研究表明， 显示交替构象（与不同的复合物一致）， 与不同的核RNA和细胞质膜相关联 细胞器需要它的功能。我们已经证明了 亨廷顿蛋白水平，暗示它在生理收养的多样性， 改变了细胞内稳态在续约期间，我们的目标是 描述HD发病机制的两个组成部分。探讨 特异性元素，我们将更精确地定义亨廷顿蛋白的正常 功能，将其置于RNA蛋白能量途径中，并描绘出 对纹状体神经元的代谢很重要的调节特征。以限定 多聚谷氨酰胺组分，我们将评估修饰和相互作用 突变亨廷顿蛋白所特有的，测试改变其异常行为的因素， 并评估生理调节的作用。我们的长期目标 继续详细了解房屋署的初步步骤， 致病级联，以便能够针对特定的过程， 为这种悲惨的疾病开发有效的治疗方法。

DESCRIPTION (Investigator's abstract): Huntington's disease (HD) is a dominant inherited neurodegenerative disorder that affects 1 in 10,000 in the U.S. Knowledge of the HD mutation, a CAG expansion that extends a run of glutamines in huntingtin, has spurred elucidation of the HD pathogenic mechanism and related polyglutamine disorders. Mutant huntingtin's HD pathogenic-trigger comprises two components: a novel toxicity property of polyglutamine conferred on the amino terminus and another intrinsic feature of the 350 kDa protein that renders striatal neurons especially vulnerable. By inserting HD CAG repeats into the mouse's HD gene (Hdh), we have uncovered abnormal conformational properties of full-length mutant huntingtin that precede truncated-aggregate and neuronal atrophy. The striatal neuron specificity, dominance and glutamine progressively implicate these events early in the human disease. We have demonstrated by Hdh inactivation and studies in striatal cells that huntingtin displays alternate conformations (consistent with distinct complexes) that associate with different sets of nuclear RNA and cytoplasmic membrane organelles that require its function. We have demonstrated regulation of huntingtin levels that implicates it in a diversity of physiologic adoptions to altered cellular homeostasis. In the renewal period, we aim to pursue the delineation of both components of HD pathogenesis. To investigate the specificity element, we will more precisely define huntingtin's normal function, placing it within the RNAprotein energy pathway and delineating regulatory features important to the metabolism of striatal neurons. To define the polyglutamine component, we will assess modifications and interactions unique to mutant huntingtin, test factors that modify its abnormal behaviors and assess the contribution of physiologic regulation. Our long-term goal continues to be a detailed understanding of the initial steps of the HD pathogenic cascade in order to be able to target specific processes for the development of effective therapies for this tragic disorder.