Tau Degradation Pathways

Tau 降解途径

• 批准号: 7117107
• 负责人: KENNETH Stephen KOSIK
• 金额: $ 21.26万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7117107
• 关键词: Alzheimer' s disease; SDS polyacrylamide gel electrophoresis; aging; biological signal transduction; conformation; enzyme activity; immunocytochemistry; immunoprecipitation; ligase; mass spectrometry; molecular chaperones; neural degeneration; neurofibrillary tangles; phosphorylation; proteasome; protein degradation; protein folding; tau proteins; ubiquitin; western blottings

DESCRIPTION (provided by applicant): The tau protein in the Alzheimer neurofibrillary tangle has been recognized for many years as a substrate for ubiquitination. More recently impaired proteasomal degradation has emerged as a theme related to many neurodegenerative diseases. In all the diseases with ubiquitinated inclusions, the relationship of the impaired degradation to the clinical disease remains uncertain. The evidence on this issue spans from the idea that the inclusions harm cells for a variety of reasons from triggering apoptosis to sequestering proteins of the ubiquitin pathway to the opposite idea that the inclusions are protective against some more toxic protofibrillar form of a self-assembled protein. Our goal for this proposal is to identity the specific modifications of tau that trigger ubiquitination and the specific proteins in the pathway that lead to tau ubiquitination. The delineation of this pathway represents an initial step toward understanding the role of tau ubiquitination in the pathogenesis of Alzheimer's disease and the tauopathies. We have amassed considerable preliminary data in support of the aims. Briefly, these findings are (a) tau phosphorylation represents a recognition signal for the tau E3 ligase; (2) the tau E2 ubiquitin conjugating enzyme is UbcH5B; (3) the tau complex which undergoes ubiquitination includes several chaperone proteins and their presence suggests a pathway that involves the E3 ligase CHIP (carboxyl terminus of Hsc70-interacting protein); (4) having detected several chaperone proteins by mass spectroscopy CHIP was identified immunocytochemically in the fraction with tau ubiquitin ligase activity. Often the pathway to the proteasome requires a collaboration between the ubiquitin-proteasome and chaperone systems. Because chaperone proteins have been identified in screens that rescue cells containing inclusions, understanding this pathway may be critical to devising therapeutic opportunities.

描述（由申请人提供）： 阿尔茨海默氏症神经原纤维缠结中的tau蛋白多年来被认为是泛素化的底物。最近，蛋白酶体降解受损是与许多神经退行性疾病有关的主题。在所有具有泛素化夹杂物的疾病中，降解与临床疾病的关系的关系仍然不确定。关于这个问题的证据涵盖了从触发凋亡到隔离泛素途径的隔离蛋白的各种原因的想法，即覆盖物具有针对某种更具毒性的原始原纤维形式的自我组装蛋白的相反观念。该提案的我们的目标是识别触发泛素化和导致tau泛素化的途径的特定修饰。该途径的描述代表了理解tau泛素化在阿尔茨海默氏病和陶氏病发病机理中的作用的第一步。我们积累了大量的初步数据，以支持目标。简而言之，这些发现是（a）tau磷酸化表示tau e3连接酶的识别信号。 （2）tau e2泛素结合酶是ubch5b; （3）经历泛素化的Tau复合物包括几种伴侣蛋白，它们的存在表明涉及E3连接酶芯片（HSC70相互作用蛋白的羧基末端）的途径； （4）通过质谱芯片检测到几种伴侣蛋白的蛋白质在用tau泛素连接酶活性的馏分中鉴定出免疫细胞化学化学。通常，通往蛋白酶体的途径需要泛素 - 蛋白酶体和伴侣系统之间的协作。由于伴侣蛋白已在拯救包含包含物的细胞的筛选中鉴定出来，因此了解该途径对于设计治疗机会至关重要。