The role of HspB8 (Hsp22) in maintaining tau proteostasis

HspB8 (Hsp22) 在维持 tau 蛋白稳态中的作用

• 批准号: 10066167
• 负责人: Jarreau Harrison
• 金额: $ 4.55万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2023-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10066167
• 关键词: Affect; Age; Aging; Alzheimer' s Disease; Attenuated; Autophagocytosis; Autophagosome; BAG3 gene; BCL2 gene; Bilateral; Binding; Binding Sites; Biological Assay; Brain; Cell Nucleus; Cell model; Cerebellum; Cytomegalovirus; Data; Degradation Pathway; Development; Disease; Female; Fiji; Foundations; Functional disorder; Heat shock proteins; Hippocampus (Brain); Human; Immunoblotting; Immunohistochemistry; Impairment; Injections; Knowledge; Label; Light; Lysosomes; Measures; Mediating; Modeling; Molecular; Molecular Chaperones; Mus; Mutate; Neurites; Neurodegenerative Disorders; Neurons; Pathogenesis; Pathologic; Pathology; Pathway interactions; Physiological Processes; Play; Population; Predisposition; Proteins; Quality Control; Reactive Oxygen Species; Reporter; Resistance; Risk Factors; Rodent; Role; Sampling; Site; Solubility; Stains; Stress; System; Testing; Time; Transcript; Work; aged; differential expression; excitatory neuron; in vivo; inhibitory neuron; insight; knock-down; male; mouse model; neuronal cell body; prevent; protein TDP-43; protein aggregation; protein degradation; proteostasis; response; small hairpin RNA; supernova; tau Proteins; tau aggregation; tau-1; transcriptome sequencing

Age is the primary risk factor for numerous neurodegenerative diseases, with Alzheimer’s disease (AD) being the most prevalent. During aging there is a decline in protein quality control systems which likely contributes to the formation of the molecular hallmarks of AD; with the accumulation of pathological tau species being a key feature of the disease. Dysfunction of autophagy and mechanisms that promote protein solubility occur early in the pathogenesis of AD. Impairment of these pathways likely contributes to the accumulation and mislocalization of tau, which plays a fundamental role in the pathogenesis of AD. Recent data provide compelling evidence that the stress responsive, small heat shock protein B8 (HspB8) plays a key role in maintaining proteostasis; decreased levels result in increases in insoluble proteins and decreases in autophagy. In addition, a recent study revealed that HspB8 and the multidomain Bcl2 associated athanogene 3 (BAG3) are expressed at higher levels in inhibitory neurons which are more resistant to tau pathology. These findings are very intriguing given that HspB8 is a key binding partner of BAG3, and thus they may work together to promote tau proteostasis. Further, our preliminary data suggest that HspB8 likely plays a key role in maintaining tau solubility and promoting autophagy. The UNDERLYING PREMISE of this proposal is that in neurons HspB8 plays a critical role in mediating tau solubility and autophagy, and thus the turnover of tau. The importance of HspB8 in mediating neuronal proteostasis is illustrated by the fact that previous findings indicate that HspB8 facilitates the autophagic clearance of disease relevant, aggregate prone proteins such as truncated TDP-43 species. Nonetheless, our understanding of how HspB8 regulates tau clearance and solubility is very limited. CRITICAL KNOWLEDGE GAPS include: how HspB8 levels affect tau solubility and accumulation, the role of HspB8 in modulating autophagic flux/ autophagosome-lysosome fusion, and if the expression level of HspB8 in neuronal populations correlates with their relative susceptibility to tau pathology. Considering these critical knowledge gaps the OVERALL HYPOTHESIS of this proposal is that HspB8 plays a role in maintaining tau solubility and facilitating autophagic flux, and thus tau clearance. In the context of this overall hypothesis the specific aims of this proposal are: (1) To test the hypothesis that HspB8 mediates tau solubility and autophagic flux and thus contributes to tau clearance in a BAG3 dependent manner, (2) To test the hypothesis that HspB8 is differentially expressed in inhibitory and excitatory neurons which plays a role in determining susceptibility to tau pathology, and (3) To test the hypothesis that HspB8 protects neurons from tau pathology in vivo. The majority of these studies will be carried out using primary neuron cultures and mouse models. All in vivo studies will be carried out in older male and female mice since age likely influences the effects of HspB8. The IMPACT of these studies will be to provide crucial new insights into the mechanisms by which HspB8 protects against tau accumulation and facilitates turnover by autophagy to maintain a healthy neuron.

年龄是许多神经退行性疾病的主要危险因素，而阿尔茨海默氏病（AD）是 最普遍的。在衰老期间，蛋白质质量控​​制系统的下降可能有助于 AD分子标志的形成；病理性tau物种的积累是关键 疾病的特征。自噬和促进蛋白质可溶的机制的功能障碍 AD的发病机理。这些途径的损害可能导致积累和错误定位 tau的作用，在AD的发病机理中起着基本作用。最近的数据提供了令人信服的证据 应力敏感的小热激蛋白B8（HSPB8）在维持蛋白质的情况下起着关键作用。 扩大水平会导致不溶性蛋白质的增加和自噬的减少。此外，最近的一项研究 揭示了HSPB8和多域Bcl2相关的Athanogene 3（BAG3）以较高的水平表示 在抑制性神经元中对TAU病理更具耐药性。考虑到这些发现非常有趣 HSPB8是BAG3的关键结合伙伴，因此它们可以共同努力促进tau蛋白质抗体。更远， 我们的初步数据表明，HSPB8可能在维持tau可溶性和促进中起关键作用 自噬。该提议的基本前提是，在神经元中，hspb8在 介导tau的溶解度和自噬，从而介导tau的营业额。 HSPB8在中介中的重要性 神经元蛋白质抑制了以下事实，即先前的发现表明HSPB8促进了自噬 疾病相关的清除，易于蛋白质的蛋白质（例如TDP-43种）。尽管如此，我们的 了解HSPB8如何调节TAU清除率和溶解度非常有限。批判知识 差距包括：HSPB8水平如何影响tau的可溶性和积累，HSPB8在调制中的作用 自噬通量/自噬体 - 散糖体融合，以及神经元种群中HSPB8的表达水平 与他们对TAU病理学的相对敏感性相关。考虑这些关键知识差距 该提案的总体假设是HSPB8在维持tau溶解度和促进中起作用 自噬通量，因此清除。在这个总体假设的背景下，该提案的具体目的 为：（1）测试HSPB8介导Tau溶解度和自噬通量的假设，从而有助于Tau 以Bag3依赖方式进行清除，（2）测试HSPB8在 抑制性和兴奋性神经元在确定tau病理易感性方面起作用，（3）测试 HSPB8保护神经元免受体内tau病理的假设。这些研究中的大多数将是 使用原发性神经元培养和小鼠模型进行。所有体内研究都将在老年男性中进行 和雌性小鼠以来可能会影响HSPB8的影响。这些研究的影响是提供 对HSPB8防止TAU积累和促进的机制的关键新见解 自噬的营业额维持健康的神经元。