Convergence of tauopathy and Huntington's disease through selective autophagy

tau蛋白病和亨廷顿病通过选择性自噬的融合

• 批准号: 9422649
• 负责人: Sheng Zhang
• 金额: $ 60.65万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-30 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9422649
• 关键词: Affect; Alzheimer' s Disease; Alzheimer' s disease model; Animal Model; Autophagocytosis; Autophagosome; Behavioral; Biochemical; Biogenesis; Biological Assay; Biological Models; Brain; Brain Diseases; Cell model; Cell physiology; Cells; Cellular Stress; Clinical; Corpus striatum structure; Degenerative Disorder; Dependency; Development; Disease; Drosophila genus; Excision; Experimental Models; Foundations; Frontotemporal Dementia; Future; Genes; Genetic; Glutamine; Homologous Gene; Human; Huntington Disease; Huntington gene; Impaired cognition; Impairment; In Vitro; Joints; Knockout Mice; Lead; Length; Link; Lysosomes; Mammalian Cell; Mediating; Mediator of activation protein; Mitochondria; Modeling; Molecular Probes; Morbidity - disease rate; Movement Disorders; Mus; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Pathogenicity; Pathologic; Pathology; Pathway interactions; Patients; Pharmacology; Phenotype; Physiological; Post-Translational Protein Processing; Prevention; Property; Prosencephalon; Protein-Serine-Threonine Kinases; Recording of previous events; Reporting; Role; Sampling; Severity of illness; Starvation; Stretching; Synapses; System; Tauopathies; Testing; Therapeutic; Toxic effect; Transgenic Mice; base; combat; fly; in vivo; insight; misfolded protein; mortality; mouse model; multidisciplinary; mutant; neurodegenerative phenotype; neurotoxicity; novel; polyglutamine; postnatal; preference; prevent; receptor; scaffold; tau Proteins; tau aggregation; tau dysfunction; tau mutation; tool; wasting

Abnormal accumulation of misfolded Tau protein is tightly linked pathogenically to a group of brain degenerative disorders including Alzheimer's disease (AD) that are collectively called Tauopathies. Currently there is no effective prevention or treatment avenue against these debilitating diseases. Targeted clearance of misfolded, pathogenic Tau species thus represents one potentially vital therapeutic strategy. A flurry of recent studies, corroborating with a long history of clinical observations, have led to the proposal that Huntington's disease (HD), another fatal neurodegenerative disorder caused by an abnormal expansion of a glutamine tract (polyQ) in Huntingtin (HTT) protein, is also a tauopathy disease. Interestingly, while working on the HTT homolog in Drosophila, we found that normal HTT can promote the clearance of certain misfolding-prone Tau species by acting as a scaffold in selective autophagy, a subtype of autophagy-lysosomal pathway that requires cargo receptors such as p62/SQSTM1 to recognize and target specific cytosolic components for lysosomal degradation. Subsequent studies in mammalian cells and in mouse AD models further supported this finding, which, together with the known autophagic phenotypes in HD cells and in mice expressing polyQ-deleted HTT, suggest a scenario that polyQ expansion in HTT disrupts its own activity in promoting selective autophagy and normal Tau turnover, leading to the Tau pathology. Such a hypothesis not only supports the HTT-mediated autophagy pathway as a converging mechanism linking HD and Tauopathy, but also raises the promise of harnessing this conserved innate protective pathway for targeted removal of pathogenic Tau in Tauopathies. In this joint R01 application, we will use our established assays in the complementary Drosophila, cellular, and mouse model systems to rigorously and systematically test this hypothesis at the genetic, biochemical and functional levels. Taking advantage of the conserved HTT and autophagy pathways, as well as the availability of a plethora of Tau models and Tau toxicity assays established in Drosophila, we will use flies as an in vivo tool to evaluate the effect of polyQ lengths on the autophagic function of HTT, and to examine the discrete Tau species to search for the ones that can be degraded by the HTT-mediated selective autophagy and for their common signatures; Using mammalian cell-based assays, we will validate the findings from the flies and also probe the molecular mechanisms underlying the modulatory role of the polyQ stretch on HTT activities. Finally, by manipulating Tau and HTT in the well-characterized mouse HD and AD models, we will directly validate our hypothesis and findings in an in vivo setting that is physiologically closer to humans. Completion of this project will reveal novel mechanistic insight into the crosstalk between Tauopathy and HD, and establish the feasibility of future pharmacological exploitation of the novel selectively autophagy pathway to combat morbidity and mortality arising from Tau-associated AD and other Tauopathies.

错误折叠的Tau蛋白异常堆积与一组脑退行性变密切相关 包括阿尔茨海默病(AD)在内的疾病统称为tauopathies。目前没有 针对这些衰弱疾病的有效预防或治疗途径。有针对性地清除折叠错误， 因此，致病性Tau物种代表了一种潜在的重要治疗策略。最近的一系列研究， 与长期的临床观察相印证，导致了亨廷顿病(HD)， 另一个由谷氨酰胺束异常扩张(PolyQ)引起的致命性神经退行性疾病 亨廷顿蛋白(HTT)，也是一种肌萎缩侧索硬化症。有趣的是，在研究HTT同源时， 我们发现，正常的HTT可以通过以下方式促进某些易错折叠的Tau物种的清除 作为选择性自噬的支架，自噬-溶酶体途径的一种亚型，需要货物 受体，如p62/SQSTM1，识别和靶向溶酶体降解的特定胞浆成分。 随后在哺乳动物细胞和小鼠AD模型中的研究进一步支持了这一发现，这些研究加在一起 根据HD细胞和表达多Q缺失HTT的小鼠中已知的自噬表型，提出了一种情况 HTT的多Q扩张扰乱了其自身促进选择性自噬和正常Tau周转的活动， 导致了Tau的病理。这样的假设不仅支持HTT介导的自噬途径作为一种 连接HD和直立面疗法的汇聚机制，但也提高了利用这种保守的先天机制的前景 靶向清除牛磺酸的保护性途径。在此联合R01应用程序中，我们将 使用我们在互补的果蝇、细胞和小鼠模型系统中建立的检测方法，严格 并在遗传、生化和功能水平上对这一假说进行系统检验。利用这一优势 保守的HTT和自噬途径，以及过多的Tau模型和Tau毒性 在果蝇中建立的检测，我们将使用苍蝇作为体内工具来评估多聚Q长度对 HTT的自噬功能，并检查离散的Tau物种以寻找可降解的Tau物种 通过HTT介导的选择性自噬和它们的共同特征；使用基于哺乳动物细胞的分析， 我们将验证果蝇的发现，并探索这种调节的分子机制 多聚Q伸展在HTT活动中的作用。最后，通过在特征良好的小鼠中操作Tau和HTT HD和AD模型，我们将在生理学的活体环境中直接验证我们的假设和发现 更接近人类。该项目的完成将揭示对串扰的新的机械洞察力 并为今后有选择性地开发该药的药理作用奠定了可行性 自噬途径，以对抗Tau相关AD和其他自噬疾病引起的发病率和死亡率。