Deubiquitinase USP11 in tau regulation and age-related tauopathy

去泛素酶 USP11 在 tau 调节和年龄相关 tau 病中的作用

• 批准号: 10515873
• 负责人: David E Kang
• 金额: $ 34.15万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10515873
• 关键词: Deubiquitinase; USP11; tau; regulation; age

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.

微管相关蛋白 tau (MAPT) 在多个 神经退行性疾病，包括阿尔茨海默氏病 (AD)，tau 蛋白积累异常会导致这种疾病。 与神经元损失、突触相关的神经原纤维缠结的寡聚化和形成 而 tau 蛋白会经历不同的翻译后修饰。 包括磷酸化、乙酰化和泛素化，泛素化对于 tau 蛋白的周转至关重要 泛素-蛋白酶体系统和自噬-溶酶体途径已知 Tau 被泛素化。 各种 E3 连接酶，包括 CHIP、TRAF6 和 MARCH7，但对其作用知之甚少。 去泛素酶 (DUB) 在调节 tau 功能、周转或 tau 病中的作用。 基因组编码 >90 个 DUB 泛素特异性肽酶 (USP) 是最大的 DUB 家族。 在人类中包含约 50 个成员，其中 27 个在中枢神经系统中表达。 对 CNS 表达的 DUB 的无偏筛选发现 USP11 和 USP13 是 tau 的正调节因子。 通过利用小鼠模型和人类死后组织以及分子、细胞 生物学、成像、生物化学、电生理学、行为学、病毒、组织化学和重组 蛋白质工具集，该提案将 1. 验证 USP11 在 tau 发病机制中作为年龄函数的作用 和体内性别，以及 2. 确定 USP11 在 tau 稳定性、聚集和 转基因神经元和体外系统的毒性。 这些研究的成功结束将确定 USP11 及其 DUB 的重大贡献 人类和小鼠体内的 tau 蛋白病变与衰老和性别有关。 解释了人类和小鼠 tau 蛋白病严重程度的潜在性别差异。 与 RanBP9 一起，在 tau 修饰中，将为 USP11 DUB 活动提供新颖的机制见解 和毒性。