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蛋白的异常积累在病原上与一组脑退化密切相关 包括阿尔茨海默氏病（AD）在内的疾病，这些疾病统称为tauopathies。目前没有 有效预防或治疗途径，以防止这些使人衰弱的疾病。有针对性的错误折叠， 因此，致病性Tau物种代表了一种潜在的重要治疗策略。一系列最近的研究， 凭借悠久的临床观察历史证实，导致了亨廷顿氏病（HD）， 另一个致命的神经退行性疾病是由谷氨酰胺道（Polyq）异常膨胀引起的 Huntingtin（HTT）蛋白也是一种tauopathy疾病。有趣的是，在研究HTT同源物的同时 果蝇，我们发现正常的HTT可以通过 充当选择性自噬的脚手架，这是需要货物的自噬 - 溶糖途径的亚型 诸如p62/SQSTM1之类的受体识别并靶向特定的胞质成分以溶酶体降解。 随后在哺乳动物细胞和小鼠AD模型中进行的研究进一步支持了这一发现，这共同 在HD细胞中的已知自噬表型和表达PolyQ删除HTT的小鼠中，提出了一种情况 HTT中的PolyQ扩展破坏了其自身在促进选择性自噬和正常TAU周转方面的活动， 导致tau病理学。这样的假设不仅支持HTT介导的自噬途径 连接高清和tauopathy的融合机制，但也提出了利用这种保守的先天物的希望 针对靶向去除致病性tau的保护途径。在此联合R01应用中，我们将 在互补的果蝇，蜂窝和小鼠模型系统中使用我们已建立的测定 并在遗传，生化和功能水平上系统地检验了这一假设。利用 保守的HTT和自噬途径，以及众多Tau模型和TAU毒性的可用性 在果蝇中建立的测定法，我们将使用苍蝇作为体内工具，以评估Polyq长度对 HTT的自噬功能，并检查离散的Tau物种以搜索可以降解的物种 由HTT介导的选择性自噬及其共同特征；使用基于哺乳动物的细胞测定法， 我们将验证苍蝇中的发现，并探测调节型基础的分子机制 polyq伸展在HTT活动中的作用。最后，通过操纵良好的小鼠中的tau和htt 高清和广告模型，我们将在生理上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机械洞察力 Tauopathy和HD，并建立了对小说的未来药理剥削的可行性 与Tau相关的AD和其他Tauopathies引起的自噬途径与发病率和死亡率作斗争。