CELLULAR PATHOGENIC MECHANISMS IN HUNTINGTON'S DISEASE

亨廷顿氏病是一种破坏性的神经退行性疾病，是一种常染色体显性遗传。致病等位基因编码亨廷顿蛋白（htt）氨基末端区域扩展的多聚谷氨酰胺束，htt是一种正常功能未知的大蛋白质。这个提议中的统一假设是，含有扩展的多聚谷氨酰胺束（htt-ex）的htt通过不可逆地阻断蛋白酶体而引起蛋白酶体中毒。我们认为，中毒的蛋白酶体在有丝分裂后的神经元的正常蛋白质周转失败，细胞功能障碍和死亡的结果。野生型htt（htt-wt）不应产生这种效应。拟议的研究将不仅考虑中毒-蛋白酶体假说，而且考虑替代假说，其中htt-ex的致病作用不依赖于蛋白酶体。我们围绕三个具体目标组织了这些研究：1。目的：探讨htt-ex基因表达的细胞内分布及致病作用是否随细胞类型和增殖状态而变化。2.检测htt-ex表达对蛋白酶体功能和特定蛋白质（包括htt本身）周转的影响。3.研究htt-ex表达对神经元功能的影响，并确定已知的蛋白酶体抑制剂是否可以模拟这些作用。在这三组实验的结论中，我们将知道1）蛋白酶体的位置和功能是否响应于细胞周期和htt表达而改变;（2）htt是否直接或间接地影响蛋白酶体功能和蛋白质周转;（3）htt-ex是否改变分裂和静止分化细胞的细胞功能;和（4）蛋白酶体抑制剂是否模拟HTT-EX诱导的神经元功能变化。

Huntington's disease is a devastating neurodegenerative disease that is inherited as an autosomal dominant. Disease-causing alleles encode expanded polyglutamine tracts in the aminoterminal region of huntingtin (htt), a large protein whose normal function is unknown. The unifying hypothesis in this proposal is that htt containing an expanded polyglutamine tract (htt-ex) causes proteasome poisoning by irreversibly blocking proteasomes. We argue that poisoned proteasomes in postmitotic neurons results in a failure of normal protein turnover and in cell dysfunction and death. Wild-type htt (htt-wt should not produce such effect. The proposed studies will consider not only the poisoned- proteasome hypothesis but also alternative hypotheses, in which the pathogenic action of htt-ex does not depend on proteasomes. We have organized these studies around three Specific Aims: 1. To determine whether the intracellular distribution and the pathogenic effects of htt-ex expression vary with cell type and proliferative state. 2. To examine the effect of htt-ex expression on proteasome function and on the turnover of specific proteins, including htt itself. 3. To examine the effects of htt-ex expression on neuronal function and to determine whether known proteasome inhibitors can mimic these effects. At the conclusion of these three sets of proposed experiments we will know 1) whether proteasome location and function change in response to cell cycle and htt expression; (2) whether htt affects proteasome function and protein turnover either directly or indirectly; (3) whether htt-ex alters cellular function in dividing and stationary, differentiated cells; and (4) whether proteasome inhibitors mimic htt-ex-induced changes in neuronal function.