Divergent roles of Slingshot-1 in tauopathy

Slingshot-1 在 tau 蛋白病中的不同作用

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos 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

项目摘要

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）和功能障碍的线粒体的积累与包括阿尔茨海默氏病（AD）在内的多种神经退行性疾病中的合成和神经元丧失有关。这种间隙缺陷被认为很大程度上是由于自噬 - 散热体系统中的缺陷而产生的。虽然安装实验证据至少在部分驱动的Aβ中支持了AD是aβ的观念，但在机械上将Aβ和TAU发病机理的方式上仍然存在一个考虑的知识差距。我们最近发表的初步研究表明，弹弓同源1（SSH1）途径构成了Aβ与Tau发病机理之间的关键联系。 SSH1是一种蛋白质磷酸酶，以其Cofilin去磷酸化活性而闻名。 SSH1通过氧化应激（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。然后活化的cofilin可以几个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凋亡。同样，我们发现SSH1和Cofilin的激活是Aβ42诱导的线粒体功能障碍，突触损失以及在LTP中定义的井以及/或在发病机理的细胞和小鼠模型中定义的井（APP/PS1）中所必需的。为了支持这些实验发现，App/PS1小鼠大脑以及AD大脑线粒体中的App/PS1小鼠大脑中，活化的Cofilin和SSH1/Cofilin络合物都会增加。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具有模块化和独立的活性，该活性可调节自噬和TAU清除率。通过利用分子，生化，细胞生物学，病毒和组织化学工具，我们建议（1）在p62介导的自噬和线粒体中剖析SSH1的模块化活性；（2）确定SSH1在体内p62介导的自噬和tauopathy中的作用。