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：
10548201
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 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10548201
关键词：
Abeta synthesis Ablation Address Alzheimer&apos s Disease Alzheimer&apos s disease brain Amyloid beta-Protein 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 Polymers 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 beta-arrestin desensitization gamma secretase hyperphosphorylated tau in vivo indexing inhibition of autophagy insight interdisciplinary approach neuroinflammation neuronal cell body neurotransmission novel polymerization 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.

阿尔茨海默病 (AD) 的主要病理特征是 β 淀粉样蛋白 (Aβ) 和过度磷酸化的 tau 蛋白（即 β2AR、GPR3、AT2R、CXCR2、和 NMDAR）已被证明在 AD 发病机制中发挥着不可或缺的作用，但尚不清楚。关于多种 GPCR 如何对 Aβ 和 tau 发病机制产生积极影响以及鉴于 GPCR 通过 β-arrestin 具有共同的作用机制。支架信号复合物，中心假设是 β-arrestins 的作用 GPCR 的下游直接影响 AD 发病机制。在细胞中；1) 游离未结合，2) GPCR 结合，3) 微管结合，每种都有不同的信号传导先前的研究表明，AD 大脑中的 β-arrestins 表达上调，并且 β-arrestins 的表达上调。然而，β-抑制蛋白是否以及如何促进 Aβ 发病机制尚不清楚。初步数据表明，AD 中的 tau 蛋白病和神经变性受到病理影响。 β-arrestin 寡聚体通过 2 种不同的机制促进 tau 蛋白病：1) 直接与 tau 蛋白竞争与微管 (MT) 结合，从而解除 MT 动力学的调节 2) 抑制 tau 清除；通过解除自噬机制的管制。通过分子利用、细胞生物学、生物化学、电生理学、行为学、病毒学和组织化学工具，该提案将 1) 验证 β-arrestins 在体内 tau 蛋白病中的作用，2) 验证 β-arrestins 在 tau/微管动力学中的作用，以及 3) 研究 β-arrestins 的作用 p62 介导的自噬和 tau 更新中的抑制蛋白该提案将验证 β- 是否存在。视紫红质抑制蛋白及其寡聚体状态可作为减轻 tau 蛋白的有希望的治疗靶点发病。