Tau Degradation Pathways

描述（由申请人提供）： 阿尔茨海默氏症神经元缠结中的tau蛋白多年来一直被认为是泛素化的底物。最近，受损的蛋白酶体降解已经成为与许多神经退行性疾病相关的主题。在所有具有泛素化包涵体的疾病中，受损的降解与临床疾病的关系仍然不确定。关于这个问题的证据涵盖了从内含物因各种原因伤害细胞的想法，从触发细胞凋亡到隔离泛素途径的蛋白质，到相反的想法，即内含物对一些更具毒性的自组装蛋白质的原纤维形式具有保护作用。我们这项提议的目标是确定触发泛素化的tau蛋白的特定修饰以及导致tau蛋白泛素化的途径中的特定蛋白质。该通路的描绘代表了理解tau泛素化在阿尔茨海默病和tau蛋白病发病机制中的作用的第一步。我们已经收集了大量的初步数据来支持这些目标。简言之，这些发现是（a）tau磷酸化代表tau E3连接酶的识别信号;（2）tau E2泛素缀合酶是UbcH 5 B;（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CHIP的途径（Hsc 70-相互作用蛋白的羧基末端）;（4）通过质谱检测到几种伴侣蛋白，在具有tau泛素连接酶活性的级分中免疫细胞化学鉴定CHIP。通常，通向蛋白酶体的途径需要泛素-蛋白酶体和分子伴侣系统之间的协作。由于伴侣蛋白已在拯救含有内含物的细胞的筛选中被鉴定出来，因此了解这一途径对于设计治疗机会可能至关重要。

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.