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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

基本信息

批准号：
10600991
负责人：
David E Kang
金额：
$ 40.25万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
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/10600991
关键词：
Acetylation Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease brain Antibodies Autophagocytosis Autopsy Axonal Transport Behavioral Binding Biochemical Biological Biological Assay Biosensor Brain Cells Complex Cycloheximide Defect Deubiquitination Electrophysiology (science)Enzymes Family Female Fluorescence Resonance Energy Transfer Frontotemporal Dementia Frontotemporal Lobar Degenerations Functional disorder Gene Dosage Genetic Models Human Human Genome Image Impaired cognition Impairment In Vitro Link Lysosomes Mediating Messenger RNA Modification Molecular Mus Neurodegenerative Disorders Neurons Outcome Pathogenesis Pathology Pathway interactions Patients Peptide Hydrolases Phenotype Phosphorylation Post-Translational Protein Processing Proteins Recombinant Proteins Regulation Role Scaffolding Protein Severities Sex Differences Slice Synapses Synaptic plasticity System TRAF6 gene Tauopathies Testing Tissues Toxic effect Transgenic Mice Ubiquitin Ubiquitination Viral X Chromosome age related experimental study in vivo insight male member mouse model multicatalytic endopeptidase complex mutant neurofibrillary tangle formation neuroinflammation neuron loss neurotoxicity novel sarkosyl scaffold sex tau Proteins tau aggregation tau function tau mutation tau-1 ubiquitin isopeptidase ubiquitin-protein ligase

项目摘要

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）聚集并积累在多个细胞中。神经退行性疾病，包括阿尔茨海默病（AD）。异常的tau积累导致寡聚化和形成与神经元损失、突触功能障碍和认知障碍虽然tau蛋白在翻译后经过不同的修饰，包括磷酸化、乙酰化和泛素化，泛素化对于tau蛋白通过蛋白质的转运是至关重要的。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、TRAF 6和MARCH 7。然而，人们对这个角色知之甚少。去泛素化酶（DUBs）在调节tau蛋白功能、周转或tau蛋白病中的作用。人类基因组编码>90个DUB。泛素特异性肽酶（USP）是DUB中最大的家族在人类中约有50个成员。其中，27个在CNS中表达。我们的结果来自一个 CNS表达的DUB的无偏筛选将USP 11和USP 13鉴定为tau的正调节剂。利用小鼠模型和人死后组织，生物、成像、生物化学、电生理、行为、病毒、组织化学和重组蛋白质工具集，这项建议将1。验证USP 11在tau发病机制中作为年龄的函数的作用和体内性，以及2.确定USP 11在tau稳定性、聚集和遗传修饰的神经元和体外系统中的毒性。这些研究的成功结论将确定USP 11及其DUB的重要贡献活动，人类和小鼠中的tau蛋白病作为衰老和性别的函数。USP 11水平可以部分解释了人类和小鼠中tau蛋白病严重程度的潜在性别差异。此外，这些结果将为USP 11 DUB活性提供新的机制见解，与RanBP 9一致，在tau修饰中和毒性。