Divergent roles of Slingshot-1 in tauopathy

Slingshot-1 在 tau 蛋白病中的不同作用

• 批准号: 10514604
• 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/10514604
• 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; Oxidative Stress Induction; Pathogenesis; Pathway interactions; Phosphorylation; Play; Process; Protein Dephosphorylation; Protein phosphatase; Proteins; Publishing; Role; Synapses; System; Tauopathies; Testing; Transfection; Variant; Viral; cofilin; hyperphosphorylated tau; 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.

毒性蛋白（即Aβ42和tau）的积累和功能障碍的线粒体与多种神经退行性疾病（包括阿尔茨海默病（AD））中的突触和神经元损失相关。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Aβ驱动的tau蛋白病的观点，但在Aβ和tau蛋白发病机制的机制联系方面仍存在相当大的知识缺口。我们最近发表的和初步的研究表明，弹弓同源物-1（SSH 1）通路构成了Aβ和tau发病机制之间的关键联系。SSH 1是一种蛋白磷酸酶，以其cofilin去磷酸化活性而闻名。SSH 1被氧化应激（即H2 O2、Aβ等）激活。和/或细胞内Ca 2+升高，这导致cofilin的活化/去磷酸化。激活的cofilin然后可以切断F-肌动蛋白（在突触处）和/或易位到线粒体以促进线粒体介导的凋亡。同样，我们发现，在Aβ42发病机制的细胞和小鼠模型（APP/PS1）中，Aβ42诱导的线粒体功能障碍、突触丢失以及LTP和/或学习/记忆缺陷（威尔斯）都需要SSH 1和cofilin的激活。为了支持这些实验发现，激活的cofilin和SSH 1/cofilin复合物在APP/PS1小鼠脑中增加，如同在AD脑的线粒体中的威尔斯。在初步研究中，我们发现，除了cofilin，SSH 1还包含对自噬货物受体p62的模块化和独立活性，其功能是调节自噬和tau清除。通过利用分子、生物化学、细胞生物学、病毒和组织化学工具，我们建议（1）剖析SSH 1在p62介导的自噬和线粒体自噬中的模块活性;（2）确定SSH 1在体内p62介导的自噬和tau蛋白病中的作用。