The role of HspB8 (Hsp22) in maintaining tau proteostasis

年龄是许多神经退行性疾病的主要危险因素，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，这可能是导致 阿尔茨海默病分子特征的形成；病理性tau物种的积累是关键 这种疾病的特征。自噬功能障碍和促进蛋白质溶解的机制发生在早期 AD的发病机制。这些通路的损伤可能导致积聚和错误定位 Tau在AD的发病机制中起着基础性作用。最近的数据提供了令人信服的证据 应激反应的小分子热休克蛋白B8(HspB8)在维持蛋白质稳定中起着关键作用； 水平降低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 HspB8和多结构域Bcl2相关基因3(BAG3)的表达水平较高 抑制神经元对tau病理更具抵抗力。这些发现非常耐人寻味，因为 HspB8是BAG3的关键结合伙伴，因此它们可能共同促进tau蛋白的稳定。此外， 我们的初步数据表明，HspB8可能在维持tau的溶解性和促进 自噬。这一提议的基本前提是，在神经元中，HspB8在 调节tau的溶解和自噬，从而调节tau的周转。HspB8在调解中的重要性 以前的发现表明，HspB8促进了自噬，这说明了神经元的蛋白稳定 清除与疾病相关的易聚集蛋白质，如截短的TDP-43物种。尽管如此，我们的 对HspB8如何调节tau清除和溶解度的了解非常有限。批判性知识 差距包括：HspB8水平如何影响tau的溶解和积累，HspB8在调节中的作用 自噬通量/自噬小体-溶酶体融合以及HspB8在神经元群体中的表达水平 与他们对tau病理的相对易感性有关。考虑到这些关键的知识差距， 这一提议的总体假设是，HspB8在维持tau的溶解性和促进 自噬通量，因此tau清除。在这一总体假设的背景下，这项提议的具体目标 是：(1)检验HspB8介导tau的溶解度和自噬通量并因此有助于tau的假设 以BAG3依赖的方式清除，(2)检验HspB8在 抑制性和兴奋性神经元，在确定tau病理易感性方面发挥作用，以及(3)检测 HspB8在体内保护神经元免受tau病理影响的假说。这些研究中的大多数将是 使用原代神经元培养和小鼠模型进行。所有活体研究都将在老年男性身上进行 雌性小鼠的年龄可能会影响HspB8的效果。这些研究的影响将是提供 对HspB8防止tau积累和促进 通过自噬来更新，以维持健康的神经元。

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.