Novel role of β-arrestins in Tauopathy

β-抑制蛋白在 Tau 病中的新作用

基本信息

批准号：
10373926
负责人：
JungA Alexa Woo
金额：
$ 40.25万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-15 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10373926
关键词：
Abeta synthesis Ablation Address Alzheimer&apos s Disease Alzheimer&apos s disease brain Amyloid beta-Protein Arrestins Autophagocytosis Autophagosome Axon Axonal Transport Behavioral Binding Biochemical Biological Brain Cells Complex Data Defect Deposition Distal Electrophysiology (science)Future G-Protein-Coupled Receptors GPR3 gene Genetic IL8RB gene Impaired cognition Impairment In Vitro Learning Link Lysosomes Measures Mediating Memory impairment Microfluidic Microchips Microtubule Depolymerization Microtubules Mitochondria Modeling Molecular Molecular Conformation Mus Nerve Degeneration Neurites Neurodegenerative Disorders Neurons Outcome Pathogenesis Pathogenicity Pathologic Pathology Pathway interactions Play Proteins Receptor Signaling Recombinant adeno-associated virus (rAAV)Recovery of Function Reporter Role Signal Transduction Solid Synapses Synaptic plasticity Tauopathies Testing Therapeutic Transgenic Mice Viral abeta accumulation base beta-arrestin desensitization gamma secretase hyperphosphorylated tau in vivo indexing insight interdisciplinary approach neuroinflammation neuronal cell body neurotransmission novel receptor binding receptor internalization retrograde transport scaffold tau Proteins therapeutic target tool trafficking

项目摘要

The major defining pathological hallmarks of Alzheimer’s disease (AD) are the accumulation of amyloid β (Aβ) and hyperphosphorylated tau. Multiple GPCRs (i.e, β2AR, GPR3, AT2R, CXCR2, & NMDARs) have been shown to play integral roles in AD pathogenesis. However, it is unclear as to how a diverse array of GPCRs all positively impinge on Aβ and tau pathogenesis as well as neurodegeneration in AD. Given that GPCRs share a common mechanism of action via β-arrestin scaffolding signaling complexes, the central hypothesis is that the actions of β-arrestins downstream of GPCRs directly impact AD pathogenesis. β-arrestins exist in three distinct states in cells; 1) free unbound, 2) GPCR-bound, and 3) microtubule-bound, each with different signaling capability. Previous studies have shown that β-arrestins are upregulated in AD brains and that β- arrestins promote Aβ pathogenesis. However, it is unknown whether and how β-arrestins pathogenically impinge on tauopathy and neurodegeneration in AD. Preliminary data indicate that β-arrestin oligomers promote tauopathy via 2 distinct mechanisms: 1) directly competing with tau for binding to microtubules (MT), thereby deregulating MT dynamics; 2) inhibiting tau clearance by deregulating the autophagy machinery. By utilizing molecular, cell biological, biochemical, electrophysiological, behavioral, viral, and histochemical tools, this proposal will 1) validate the role of β-arrestins in tauopathy in vivo, 2) validate the role of β-arrestins in tau/microtubule dynamics, and 3) investigate the role of β- arrestins in p62-mediated autophagy and tau turnover. This proposal will validate whether β- arrestins and their oligomeric status serve as promising therapeutic targets to mitigate tau pathogenesis.

阿尔茨海默氏病（AD）的主要定义病理标志是淀粉样β（Aβ）和高磷酸化tau。多个GPCR（即β2AR，GPR3，AT2R，CXCR2，＆nmdars）已显示在AD发病机理中起着不可或缺的作用。但是，还不清楚关于GPCR的潜水员阵列如何对Aβ和TAU发病机理产生积极影响 AD中的神经变性。鉴于GPCR通过β-arrestin具有共同的作用机理脚手架信号传导复合物，中心假设是β-arrestin的作用 GPCR的下游直接影响AD发病机理。 β-arrestin存在于三种不同的状态在细胞中； 1）自由脱落，2）绑定GPCR和3）微管结合，每个都有不同的信号传导功能。先前的研究表明，在AD大脑中进行了β-arrestin，并且β- 逮捕蛋白促进Aβ发病机理。但是，未知是否以及如何β-arrestin 在AD中，病原体对Tauopathy和神经退行性变化。初步数据表明 β-arrestin寡聚物通过2种不同的机制促进tauopathy：1）直接与tau竞争用于与微管（MT）结合，从而取消调节MT动力学； 2）抑制tau间隙通过放大自噬机械。通过使用分子，细胞生物学，生化，电生理，行为，病毒和组织化学工具，该建议将1）验证β-arrestin在体内tauopathy中的作用，2）验证β-arrestin在tau/微管动力学中的作用，3）研究β-的作用 P62介导的自噬和TAU周转率中的逮捕蛋白。该建议将验证β- 逮捕蛋白及其低聚地位是减轻tau的有前途的治疗靶标发病。