RNA binding proteins as novel targets in Alzheimer's disease

RNA结合蛋白作为阿尔茨海默病的新靶点

基本信息

批准号：
8927738
负责人：
Benjamin L Wolozin
金额：
$ 49.55万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-15 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8927738
关键词：
Alzheimer&apos s Disease Amyloid beta-Protein Area Binding Binding Proteins Biology Brain Cell Culture Techniques Chronic Code Complex Cytoplasmic Granules Employee Strikes Exhibits FTD with parkinsonism Functional disorder Heat shock proteins Image Immunochemistry Knock-out Lead Life Mass Spectrum Analysis Modification Movement Mus Nature Nerve Degeneration Neurofibrillary Tangles Neurons Pathology Pathology processes Pathway interactions Phosphorylation Physiological Post-Translational Protein Processing Process Property Proteins RNA RNA Stability RNA-Binding Proteins Regulation Research Role Signal Transduction Stress Synapses Tauopathies Testing Therapeutic Intervention Transcript Transgenic Model Translations Viral Virus biological adaptation to stress cellular imaging in vivo molecular pathology novel protein complex public health relevance receptor response spectroscopic imaging tau Proteins tau aggregation tau mutation trafficking

项目摘要

DESCRIPTION (provided by applicant): This proposal investigates a novel mechanism for the misfolding and aggregation of microtubule associated protein tau (MAPT), which we hypothesize provides an unrecognized but major aspect of the pathophysiology of tauopathies, such as Alzheimer's disease (AD). We have recently identified a new type of molecular pathology in AD that derives from the aggregation of RNA binding proteins, forming RNA-protein complexes that include stress granules. These stress granules progressively accumulate in the brains of transgenic models of tauopathy, as well as massively accumulate in subjects with AD and FTDP-17. The genesis of this research comes from the simple observations that 1) RNA binding proteins form RNA granules through a striking property of reversible aggregation, which is under physiological regulation, and 2) MAPT binds to some RNA binding proteins, including TIA-1. RNA granules consolidate transcripts for transport, storage and/or degradation. Our results suggest that TIA-1 stimulates phosphorylation and misfolding of MAPT, and that MAPT stimulates formation of TIA-1 positive stress granules; the association of MAPT with stress granules reduces its degradation and appears to stabilize insoluble MAPT. The chronic nature of AD might lead to excessive formation of stress granules and aggregation of MAPT, contributing to neurodegeneration. We hypothesize that MAPT and RNA binding proteins exhibit bidirectional regulation. MAPT promotes the formation and stability of RNA granules, including stress granules. Conversely, RNA binding proteins and the translational signaling cascade stimulate the phosphorylation, and misfolding of MAPT. This hypothesis will be studied in the context of three aims: Aim 1 will determine the mechanisms by which TIA-1 interacts with MAPT. We will use structural studies, imaging and mass spectroscopy to highlight key changes in discover key binding proteins. Aim 2 will determine the role of MAPT in neuronal RNA granule biology, including stress granules. This aim will explore this biology using live cell imaging to explore RNA granule dynamics under basal and stress conditions and will examine whether MAPT modulates the types of transcripts associated with particular RNA granules/ stress granules (using iCLIP). Finally, Aim 3 will determine whether stress granule/RNA translation pathways regulate MAPT-mediated neurodegeneration in vivo. This aim will focus on the RNA binding proteins used in our preliminary studies (e.g., TIA-1) as well as the novel MAPT/ stress granule components identified by mass spectroscopy.

描述（由申请人提供）：该提案研究了微管相关蛋白 tau (MAPT) 错误折叠和聚集的新机制，我们捕获的该机制提供了 tau 病病理生理学的一个未被认识但主要的方面，例如阿尔茨海默病 (AD)我们最近发现了 AD 中的一种新型分子病理学，它源自 RNA 结合蛋白的聚集，形成包含应激的 RNA-蛋白复合物。这些应激颗粒逐渐积聚在 tau 蛋白病转基因模型的大脑中，并在 AD 和 FTDP-17 受试者中大量积聚。这项研究的起源来自于以下简单观察：1) RNA 结合蛋白通过形成 RNA 颗粒。可逆聚集的显着特性，受到生理调节，2) MAPT 与一些 RNA 结合蛋白结合，包括 TIA-1，RNA 颗粒巩固转录物以进行运输和储存。我们的结果表明，TIA-1 刺激 MAPT 的磷酸化和错误折叠，并且 MAPT 刺激 TIA-1 阳性应激颗粒的形成；MAPT 与其降解有关，并且似乎稳定了不溶性 MAPT。 AD 的性质可能导致应激颗粒的过度形成和 MAPT 的聚集，从而导致神经退行性变。我们发现 MAPT 和 RNA 结合蛋白表现出双向调节作用。 RNA 颗粒（包括离线应激颗粒）的稳定性、RNA 结合蛋白和翻译信号级联刺激 MAPT 的磷酸化和错误折叠。目标 1 将确定 TIA- 的机制。 1 与 MAPT 相互作用。我们将使用结构研究、成像和质谱来突出发现关键结合蛋白的关键变化，目标 2 将确定 MAPT 在神经元 RNA 颗粒生物学（包括应激）中的作用。该目标将使用活细胞成像来探索这种生物学，以探索基础和应激条件下的 RNA 颗粒动力学，并将检查 MAPT 是否调节与特定 RNA 颗粒/应激颗粒相关的转录物类型（使用 iCLIP）。确定应激颗粒/RNA 翻译途径是否在体内调节 MAPT 介导的神经变性。这一目标将集中于我们初步研究中使用的 RNA 结合蛋白（例如 TIA-1）以及新型蛋白。通过质谱法鉴定 MAPT/应力颗粒成分。