Divergent roles of Slingshot-1 in tauopathy

在包括阿尔茨海默病（AD）在内的多种神经退行性疾病中，毒性蛋白（即Aβ42和tau）的积累和功能失调的线粒体与突触和神经元丧失有关。这种清除缺陷被认为在很大程度上是由自噬-溶酶体系统的缺陷引起的。虽然越来越多的实验证据支持AD是一种至少部分由a β驱动的tau病的观点，但在a β和tau发病机制之间的机制联系方面仍然存在相当大的知识差距。我们最近发表的研究和初步研究表明，Slingshot同源-1 （SSH1）通路是a β和tau发病机制之间的关键联系。SSH1是一种蛋白磷酸酶，以其cofilin去磷酸化活性而闻名。SSH1被氧化应激（即H2O2， Aβ等）和/或细胞内Ca2+升高激活，从而导致cofilin的激活/去磷酸化。激活的cofilin可以切断f -肌动蛋白（在突触）和/或转运到线粒体以促进线粒体介导的细胞凋亡。同样，我们发现在A发病机制（APP/PS1）的细胞和小鼠模型中，SSH1和cofilin的激活是Aβ42诱导的线粒体功能障碍、突触丧失以及LTP和/或学习/记忆缺陷所必需的。APP/PS1小鼠脑以及AD脑线粒体中活化的cofilin和SSH1/cofilin复合物增加，支持这些实验发现。在初步研究中，我们发现除了cofilin外，SSH1还对自噬货物受体p62具有模块化和独立的活性，其功能是调节自噬和tau清除。通过利用分子、生化、细胞生物学、病毒和组织化学工具，我们提出：(1)剖析SSH1在p62介导的自噬和有丝自噬中的模块化活性；(2)确定SSH1在体内p62介导的自噬和tau病变中的作用。

Accumulation of toxic proteins (i.e. Aβ42 & tau) and dysfunctional mitochondria are associated with synaptic and neuronal loss in multiple neurodegenerative disorders, including Alzheimer’s disease (AD). Such clearance defects are thought to arise in large part from deficits in the autophagy-lysosome system. While mounting experimental evidence supports the notion that AD is a tauopathy at least in part driven Aβ, there is still a considerable knowledge gap in the way Aβ and tau pathogenesis are mechanistically connected. Our recently published and preliminary studies indicate that the Slingshot homolog-1 (SSH1) pathway constitutes a critical link between Aβ and tau pathogenesis. SSH1 is a protein phosphatase, classically known for its cofilin dephosphorylating activity. SSH1 is activated by oxidative stress (i.e. H2O2, Aβ, etc.) and/or intracellular Ca2+ elevation, which results in activation / dephosphorylation of cofilin. Activated cofilin can then sever F-actin (at the synapse) and/or translocate to mitochondria to promote mitochondria-mediated apoptosis. Likewise, we have found that activation of SSH1 and cofilin are required for Aβ42-induced mitochondrial dysfunction, synaptic loss, as wells as deficits in LTP and/or learning/memory in cellular and mouse models of A pathogenesis (APP/PS1). In support of these experimental findings, activated cofilin and SSH1/cofilin complexes are increased in APP/PS1 mouse brains as wells as in mitochondria of AD brains. In preliminary studies, we found that in addition to cofilin, SSH1 contains a modular and independent activity on the autophagy cargo receptor p62, which functions to regulate autophagy and tau clearance. By utilizing molecular, biochemical, cell biological, viral, and histochemical tools, we propose to (1) dissect the modular activity of SSH1 in p62-mediated autophagy and mitophagy; and (2) determine the role of SSH1 in p62-mediated autophagy and tauopathy in vivo.