Divergent roles of Slingshot-1 in tauopathy

Slingshot-1 在 tau 蛋白病中的不同作用

• 批准号: 10293546
• 负责人: David E Kang
• 金额: --
• 依托单位: LOUIS STOKES CLEVELAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-10-01 至 2024-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10293546
• 关键词: APP-PS1; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Amyloid beta-42; Amyloid beta-Protein; Animal Model; Apoptosis; Autophagocytosis; Binding; Binding Sites; Biochemical; Biological; Biological Assay; Brain; C-terminal; Catalytic Domain; Cell model; Cells; Co-Immunoprecipitations; Complex; Defect; Dominant-Negative Mutation; F-Actin; Gene Expression; Homologous Gene; Hydrogen Peroxide; Impairment; Knowledge; Learning; Ligation; Link; Lysosomes; Mediating; Memory; Microtubules; Mitochondria; Molecular; Mus; Mutation; Neurodegenerative Disorders; Neurons; Outcome; Oxidative Stress; Pathogenesis; Pathway interactions; Phosphorylation; Play; Process; Protein Dephosphorylation; Protein phosphatase; Proteins; Publishing; Role; Synapses; System; Tauopathies; Testing; Variant; Viral; cofilin; in vivo; indexing; insight; mitochondrial dysfunction; mouse model; mutant; neuron loss; novel; receptor; tau Proteins; tau aggregation; tool

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.

在包括阿尔茨海默病(AD)在内的多种神经退行性疾病中，有毒蛋白(即Aβ42和tau)的积累和功能障碍的线粒体与突触和神经元的丢失有关。这种清除缺陷被认为在很大程度上是由于自噬-溶酶体系统的缺陷造成的。虽然越来越多的实验证据支持AD是一种互补性疾病，至少在一定程度上是由Aβ驱动的，但在Aβ和tau发病机制的机械联系方面仍有相当大的知识缺口。我们最近发表的初步研究表明，弹弓同源蛋白-1(Slingshot Homolog-1，SSH1)通路是A-β和tau发病机制之间的关键环节。SSH1是一种蛋白磷酸酶，经典地以其Cofilin去磷酸化活性而闻名。SSH1被氧化应激(如过氧化氢、Aβ等)激活。和/或细胞内Ca~(2+)升高，导致Cofilin的激活/去磷酸化。然后，激活的粘连蛋白可以切断F-肌动蛋白(在突触处)和/或转移到线粒体，以促进线粒体介导的细胞凋亡。同样，我们发现，在Aβ42诱导的线粒体功能障碍、突触丢失以及在A发病的细胞和小鼠模型(APP/PS1)中的LTP和/或学习/记忆缺陷中，SSH1和cofilin的激活是必需的。为了支持这些实验结果，激活的cofilin和SSH1/cofilin复合体在APP/PS1小鼠脑中以及AD脑线粒体中都增加了。在初步研究中，我们发现，除了cofilin，SSH1还在自噬货物受体p62上包含一个模块化的独立活性，该受体具有调节自噬和tau清除的功能。利用分子、生化、细胞生物学、病毒和组织化学等工具，我们建议(1)剖析SSH1在p62介导的自噬和有丝分裂吞噬中的模块活性；(2)确定SSH1在体内p62介导的自噬和有丝分裂中的作用。