CELLULAR PATHOGENIC MECHANISMS IN HUNTINGTON'S DISEASE

亨廷顿氏病是一种毁灭性的神经退行性疾病，遗传为常染色体显性遗传。致病等位基因编码亨廷顿蛋白(HTT)氨基末端区域的扩展多谷氨酰胺区，这是一种正常功能未知的大型蛋白质。这一建议中的统一假设是，含有扩展的聚谷氨酰胺束的HTT(HTT-EX)通过不可逆转地阻断蛋白酶体而导致蛋白酶体中毒。我们认为，有丝分裂后神经元中的蛋白酶体中毒会导致正常的蛋白质周转失败，并导致细胞功能障碍和死亡。野生型HTT(HTT-wt)不应该产生这样的效果。建议的研究不仅将考虑中毒蛋白酶体假说，还将考虑其他假说，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.确定HTT-EX表达在细胞内的分布和致病作用是否因细胞类型和增殖状态而异。2.检测HTT-EX的表达对蛋白酶体功能和特定蛋白(包括HTT本身)周转的影响。3.检测HTT-EX的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能模拟这些作用。在这三组拟议的实验的结论中，我们将知道1)蛋白酶体的位置和功能是否随着细胞周期和HTT的表达而改变；(2)HTT是否直接或间接地影响蛋白酶体的功能和蛋白质的周转；(3)HTT-EX是否改变分裂和静止的分化细胞的细胞功能；以及(4)蛋白酶体抑制剂是否模仿HTT-EX诱导的神经元功能的变化。

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.