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) 的病理学特征是以细胞内 tau 蛋白病为特征，异常过度磷酸化的积累和聚集微管相关蛋白 MAPT/tau 形成神经原纤维缠结 (NFT)，导致功能丧失尽管 Aβ 斑块在 AD 发病机制中起关键作用，但认知能力下降的严重程度。与新皮质 NFT 的负担最相关，因此促进积累的 tau 蛋白的清除。代表了 tau 蛋白病患者的一种有前途的治疗策略，这取决于对疾病进展过程中病理性 tau 蛋白物种降解的机制。最终目标是阐明 AD 等 tau 蛋白病如何引发和发生的复杂机制。据报道，tau 蛋白病可有效治疗。自噬-溶酶体或泛素-蛋白酶体系统的降解与 Tau 降解密切相关。其各种翻译后修饰，包括磷酸化、乙酰化和泛素化。初步研究表明，正常小鼠脑组织中tau蛋白被线性泛素链修饰，在 tau 病小鼠模型中，tau 蛋白的线性泛素化促进了 tau 蛋白的清除。我们进一步发现氧化应激可以增加去泛素酶 OTULIN。通过促进其磷酸化来发挥活性，AD 患者的脑组织中磷酸化和磷酸化均显着增加 OTULIN 的抑制可防止病理性 tau 蛋白的积累并减弱其作用。因此，我们认为线性泛素化可以促进 tau 蛋白的表达。降解，被去泛素酶 OTULIN 抑制，氧化应激激活 OTULIN，导致 OTULIN 的药理学抑制作用可能会减轻 tau 蛋白病。提出了三个具体目标来测试这一点。 Aim1 将确定线性泛素化在调节 tau 积累和神经元中的作用。 Aim2 将研究氧化应激介导的毒性并研究自噬溶酶体机制。 Aim 3 将使用系统生物学方法测试 OTULIN 诱导的 tau蛋白病的机制。开发 OTULIN 抑制剂，促进 tau 蛋白清除并减轻 tau 蛋白病动物的细胞毒性我们的研究将通过提供以下内容产生重大影响：1）调节 tau 聚集的新机制。和蛋白质毒性；2) 氧化应激和 tau 线性泛素化之间的新机制联系；3) 潜力；减轻 tau 蛋白病和认知能力下降的治疗方法，最终使 AD 患者受益。