Divergent roles of Slingshot-1 in tauopathy

Slingshot-1 在 tau 蛋白病中的不同作用

• 批准号: 10006955
• 负责人: David E Kang
• 金额: --
• 依托单位: JAMES A. HALEY 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/10006955
• 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.

有毒蛋白（即 Aβ42 和 tau）的积累和功能失调的线粒体与多种神经退行性疾病（包括阿尔茨海默氏病 (AD)）中的突触和神经元损失有关，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 tau 蛋白病，至少部分是由 Aβ 驱动的，但对于 Aβ 和 tau 蛋白的发病机制仍然存在相当大的知识差距。我们最近发表的初步研究表明，Slingshot 同源物-1 (SSH1) 通路构成了 Aβ 和 tau 发病机制之间的关键联系。SSH1 是一种蛋白磷酸酶，因其 cofilin 去磷酸化活性而闻名。 （即 H2O2、Aβ 等）和/或细胞内 Ca2+ 升高，导致激活的肌丝蛋白丝切蛋白可以切断 F-肌动蛋白（在突触处）和/或易位至线粒体以促进线粒体介导的细胞凋亡。同样，我们发现 SSH1 和丝丝蛋白丝切蛋白的激活是 Aβ42 诱导的线粒体功能障碍和突触丧失所必需的。 ，以及 A 发病机制的细胞和小鼠模型 (APP/PS1) 中的 LTP 和/或学习/记忆缺陷，激活了丝切蛋白 (cofilin)。 APP/PS1 小鼠大脑以及 AD 大脑线粒体中的 SSH1/cofilin 复合物增加。在初步研究中，我们发现除了 cofilin 之外，SSH1 还对自噬货物受体 p62 具有模块化且独立的活性。通过利用分子、生化、细胞生物学、病毒和组织化学工具来调节自噬和 tau 清除，我们建议 (1) 剖析 SSH1 的模块化活性。 p62 介导的自噬和线粒体自噬；(2) 确定 SSH1 在体内 p62 介导的自噬和 tau 蛋白病变中的作用。