CELLULAR PATHOGENIC MECHANISMS IN HUNTINGTON'S DISEASE

亨廷顿病的细胞致病机制

• 批准号: 6494939
• 负责人: ALLAN J TOBIN
• 金额: $ 5万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-01-25 至 2004-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6494939
• 关键词: Huntington's disease; apoptosis; astrocytes; cell differentiation; cell nucleus; cell proliferation; cell type; cellular pathology; chemical association; cytoplasm; cytotoxicity; endopeptidases; enzyme activity; gene expression; homopeptide; intracellular transport; nerve stem cell; neurons; neurophysiology; protease inhibitor; proteasome; protein metabolism; tissue /cell culture; ubiquitin

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.

亨廷顿舞蹈症是一种破坏性的神经退行性疾病，是常染色体显性遗传病。致病等位基因在亨廷顿蛋白 (htt) 的氨基末端区域编码扩展的多聚谷氨酰胺束，亨廷顿蛋白是一种大蛋白，其正常功能尚不清楚。该提案中的统一假设是，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导致蛋白酶体中毒。我们认为，有丝分裂后神经元中的中毒蛋白酶体会导致正常蛋白质周转失败以及细胞功能障碍和死亡。野生型 htt (htt-wt 不应产生这种效应。拟议的研究不仅会考虑中毒蛋白酶体假说，还会考虑替代假说，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这些研究： 1. 确定 htt-ex 表达的细胞内分布和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. 检查 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影响。在这三组实验结束时，我们将知道：1）蛋白酶体的位置和功能是否会因细胞周期和 htt 表达而变化； (2) htt是否直接或间接影响蛋白酶体功能和蛋白质周转； (3) htt-ex是否改变分裂细胞和静止分化细胞的细胞功能； (4) 蛋白酶体抑制剂是否模拟 htt-ex 诱导的神经元功能变化。