Deubiquitinase USP11 in tau regulation and age-related tauopathy

微管相关蛋白tau(MAPT)聚集并聚集在多个 神经退行性疾病，包括阿尔茨海默病(AD)。Tau的异常蓄积导致 与神经元丢失、突触相关的神经原纤维缠结的寡聚和形成 功能障碍和认知障碍。而tau经历了不同的翻译后修饰 泛素化包括磷酸化、乙酰化和泛素化，泛素化是tau周转的关键。 泛素-蛋白酶体系统和自噬-溶酶体途径。众所周知，tau是由 各种E3连接酶，包括CHIP、TRAF6和March7。然而，人们对这一角色知之甚少 脱泛素酶(DUBS)在调节tau功能、周转或肌病中的作用。人类 基因组编码&gt；90拷贝。泛素特异肽酶(USPS)是最大的DUB家族 由人类中的大约50个成员组成。其中，27个在中枢神经系统表达。我们的结果来自于 无偏筛选发现USP11和USP13是tau的正调控因子。 通过利用小鼠模型和人类死后组织以及分子、细胞 生物、成像、生化、电生理、行为、病毒、组织化学和重组 蛋白质工具包，这项建议将1.验证usp11在tau发病机制中的作用作为年龄的函数。 和体内性别，以及2.确定了usp11在tau稳定性、聚集性和 转基因神经元和体外系统的毒性。 这些研究的成功完成将决定USP11及其DUB的重大贡献 在人类和小鼠中，随着年龄和性别的变化，活动也会发生变化。USP11水平可能在一定程度上 解释了人类和小鼠肌萎缩侧索硬化症严重程度的潜在性别差异。此外，这些结果还表明， 将与RanBP9一起，在tau修饰中为USP11 DUB活动提供新的机制见解 和毒性。

The microtubule-associated protein tau (MAPT) aggregates and accumulates in multiple neurodegenerative diseases, including Alzheimer’s disease (AD). Abnormal tau accumulation leads to oligomerization and formation of neurofibrillary tangles associated with neuronal loss, synaptic dysfunction, and cognitive impairments. While tau undergoes different post-translational modifications including phosphorylation, acetylation, and ubiquitination, ubiquitination is critical for tau turnover via the ubiquitin-proteasome system and autophagy-lysosome pathways. Tau is known to be ubiquitinated by various E3 ligases, including CHIP, TRAF6, and MARCH7. However, very little is known about the role of deubiquitinases (DUBs) in the regulation of tau function, turnover, or tauopathy. The human genome encodes >90 DUBs. Ubiquitin specific peptidases (USPs) are the largest family of DUBs comprising ~50 members in humans. Of these, 27 are expressed in the CNS. Our results from an unbiased screen of CNS-expressed DUBs identified USP11 and USP13 as positive regulators of tau. By taking advantage of mouse models and human postmortem tissues together with molecular, cell biological, imaging, biochemical, electrophysiological, behavioral, viral, histochemical, and recombinant protein toolsets, this proposal will 1. validate the role of USP11 in tau pathogenesis as a function of age and sex in vivo, and 2. determine the mechanistic basis of USP11 in tau stability, aggregation, and toxicity in genetically modified neurons and in vitro systems. Successful conclusion of these studies will determine the significant contribution of USP11, and its DUB activity, to tauopathy in humans and mice as a function of aging and sex. USP11 levels could in part account for potential sex differences in severity of tauopathy in humans and mice. Moreover, these results will provide novel mechanistic insights to USP11 DUB activity, in concert with RanBP9, in tau modification and toxicity.