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Validation of a novel tau clearance mechanism.

验证新型 tau 清除机制。

基本信息

批准号：
10445826
负责人：
Kiran Bhaskar
金额：
$ 215.72万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10445826
关键词：
Acetylation Affect Alternative Splicing Alzheimer&apos s Disease Alzheimer&apos s disease patient Alzheimer&apos s disease therapeutic Amyloid beta-Protein Animal Model Attenuated Autophagocytosis Behavioral Brain Catalytic Domain Cell Death Cells Clinical Clinical Trials Complex Dementia Deposition Development Disease Disease Progression Genes Goals Huntington gene Immune response Impaired cognition Inflammation Link MAPT gene Mediating Memory Loss Microtubule-Associated Proteins Modeling Mus Neurodegenerative Disorders Neurofibrillary Tangles Neurons Oxidative Stress Pathogenesis Pathologic Pathologic Processes Pathology Patients Persons Pharmaceutical Preparations Pharmacology Phosphorylation Play Post-Translational Protein Processing Proteins Proteomics Proto-Oncogene Proteins c-abl Proto-Oncogenes Reporting Role Senile Plaques Severities Signal Pathway Sumoylation Pathway System Systems Biology Tauopathies Testing Therapeutic Therapeutic Effect Toxic effect Ubiquitin Ubiquitination Validation Variant base brain tissue cognitive ability cytotoxicity experience extracellular functional loss glycation glycosylation improved in vivo Model inhibitor insight mouse model neocortical neurofibrillary tangle formation neurotoxicity new therapeutic target nitration novel prevent proteotoxicity small molecule inhibitor tau Proteins tau aggregation therapeutic evaluation therapeutic target therapeutically effective transcriptome sequencing transcriptomics treatment strategy ubiquitin-protein ligase

项目摘要

Besides extracellular β-amyloid (Aβ) plaques deposition, Alzheimer’s disease (AD) is pathologically characterized by intracellular tauopathy that accumulation and aggregation of abnormally hyperphosphorylated microtubule-associated protein MAPT/tau form neurofibrillary tangle (NFT), resulting in loss of functional neurons. Although Aβ plaques play a key role in initiating AD pathogenesis, the severity of cognitive decline correlates best with the burden of neocortical NFTs. Therefore, promoting the clearance of accumulated tau represents a promising therapeutic strategy for tauopathy patients, which depends on a better understanding of the mechanisms underlying the degradation of pathological tau species during disease progression. Our ultimate goal is to elucidate the complex mechanisms underlying how tauopathies, such as AD, initiate and progress, and to develop effective therapeutic approaches to treat tauopathies. It is reported that tau can be degraded by autophagy-lysosomal or ubiquitin-proteasomal systems. Tau degradation is closely associated with its various post-translational modifications, including phosphorylation, acetylation, and ubiquitination. Our preliminary studies indicate that tau is modified by linear ubiquitin chains in normal mouse brain tissues, which were substantially decreased in tauopathy mouse models. Linear ubiquitination of tau promotes tau clearance in an autophagy-dependent manner. We further found that oxidative stress can increase deubiquitinase OTULIN activity by promoting its phosphorylation, which both are substantially increased in the brain tissues from AD patients. Inhibition of OTULIN prevented the accumulation of pathological tau species and attenuated its cytotoxicity in a tauopathy mouse model. Therefore, we hypothesize that linear ubiquitination promotes tau degradation, which is inhibited by deubiquitinase OTULIN; oxidative stress activates OTULIN, resulting in increased tau aggregation and neurotoxicity. Pharmacological inhibition of OTULIN may mitigate tauopathy progression by enhancing the clearance of tau aggregates. Three specific aims are proposed to test this hypothesis. Aim1 will determine the role of linear ubiquitination in regulating tau accumulation and neuronal toxicity and investigate the autophagic-lysosomal mechanism. Aim2 will investigate oxidative stress-mediated mechanisms during OTULIN-induced tauopathies using a systems biology approach. Aim 3 will test a newly developed OTULIN inhibitor in promoting tau clearance and mitigating its cellular toxicity in tauopathy animal models. Our studies will have a strong impact by providing: 1) novel mechanisms regulating tau aggregation and proteotoxicity; 2) new mechanistic link between oxidative stress and tau linear ubiquitination; 3) potential therapeutic approaches for mitigating tauopathy and cognitive decline, eventually benefiting AD patients.

除了细胞外β-淀粉样蛋白（Aβ）斑块沉积外，阿尔茨海默病（AD）是病理上的