The role of HspB8 (Hsp22) in maintaining tau proteostasis

年龄是许多神经退行性疾病的主要风险因素，阿尔茨海默病（AD）是 最普遍的。在衰老过程中，蛋白质质量控制系统下降，这可能有助于 AD的分子标志的形成;病理性tau蛋白种类的积累是关键 疾病的特征。自噬功能障碍和促进蛋白质溶解的机制发生在 AD的发病机制这些途径的损伤可能有助于积聚和错误定位 tau蛋白在AD的发病机制中起着重要作用。最近的数据提供了令人信服的证据， 应激反应性小分子热休克蛋白B8（HspB 8）在维持蛋白质稳态中起关键作用; 降低的水平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HspB 8和多结构域Bcl 2相关的产气基因3（BAG 3）以更高水平表达， 在对tau病理学更具抵抗力的抑制性神经元中。这些发现非常有趣，因为 HspB 8是BAG 3的关键结合伴侣，因此它们可以一起工作以促进tau蛋白质稳定。此外，本发明还 我们的初步数据表明，HspB 8可能在维持tau蛋白溶解性和促进tau蛋白表达方面起关键作用。 自噬这个提议的基本前提是，在神经元中，HspB 8在以下方面起着关键作用： 介导tau的溶解性和自噬，从而介导tau的周转。热休克蛋白B8在介导 先前的研究结果表明，HspB 8促进自噬， 清除疾病相关的、容易聚集的蛋白质，例如截短的TDP-43物质。尽管如此，我们的 对HspB 8如何调节tau清除和溶解度的理解非常有限。关键知识 GAPS包括：HspB 8水平如何影响tau蛋白的溶解度和积累，HspB 8在调节tau蛋白表达中的作用。 自噬通量/自噬体-溶酶体融合，以及神经元群体中HspB 8的表达水平 与它们对tau病理学的相对易感性相关。考虑到这些关键的知识差距， 该提议的总体假设是HspB 8在维持tau溶解性和促进tau蛋白的表达中起作用。 自噬通量，从而tau清除。在这一总体假设的背景下， （1）为了验证HspB 8介导tau蛋白溶解性和自噬通量从而促进tau蛋白表达的假设， （2）为了验证HspB 8在BAG 3依赖性的细胞中差异表达的假设， 抑制性和兴奋性神经元，其在确定对tau病理学的易感性中起作用，和（3）测试 HspB 8在体内保护神经元免受tau病变的假设。这些研究中的大多数将是 使用原代神经元培养物和小鼠模型进行。所有体内研究将在老年男性中进行 和雌性小鼠，因为年龄可能影响HspB 8的作用。这些研究的影响将提供 对HspB 8保护tau蛋白积累并促进tau蛋白积累的机制的重要新见解 通过自噬来维持健康的神经元。

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.