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.

微管相关的蛋白tau（mapt）均衡群，并积聚在多个神经退行性疾病，包括阿尔茨海默氏病（AD）。与神经元丧失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。包含phosporition，乙酰化和泛素化，泛素化对于通过Via the The The The The The The The The The The The The The The The The The The The The The The The The The The The The The Impuitiation至关重要。泛素 - 近调系统和自噬 - 赖斯体途径。各种E3连接酶，包括芯片，traf6和3月7日。 tau功能，更新或tauopathy的调节中的去泛素（DUB）基因组编码> 90个配音。包括人类的50个成员。 CNS表达的配音的无偏屏幕将USP11和USP13识别为TAU的正调节剂。通过利用小鼠模型和人类验尸组织以及分子，细胞生物学，成像，生化，电生理学，行为，病毒，组织化学和重组蛋白质工具集，该建议将1。验证USP11在Tau发病机理中的作用是年龄的函数和体内的性别，以及2。确定tau稳定性，聚合和和和转基因神经元和体外系统的毒性。这些研究的成功结论将确定USP11及其DUB的重要贡献活动，作为一个usp11级别的人类和小鼠的tauopathy可以部分这些结果是人类和小鼠的tauopathy的潜在性别差异将与ranbp9一起为USP11 DUB活动提供新颖的机械见解和毒性。