Capturing the molecular complexity of Alzheimer's disease through the lens of RNA binding proteins

神经性斑块和神经原纤维缠结是阿尔茨海默病(AD)的标志性病理， 但个别缠结或斑块的存在不足以预测退化；45%的 有斑块和缠结的老年人没有认知障碍或痴呆症。我们最近发现了一种新的 阿尔茨海默病的一种分子病理类型，源于RNA结合蛋白(RBPs)的聚集， 形成RNA-蛋白质复合体，称为RNA颗粒。微管相关蛋白tau (MAPT)与限制性商业惯例结合，与限制性商业惯例在RNA颗粒中共定位，限制性商业惯例增加MAPT错误折叠 /聚合。重要的是，降低RBP TIA1延缓了紧张症的进展，尽管增加了 MAPT聚合。我们假设MAPT络合物(可溶的或 不溶性)和RNA颗粒复合体是分子异质性的关键决定因素 阿尔茨海默病和其他肌萎缩侧索硬化症，并确定对每种类型的 疾病。我们将应用系统生物学方法，将蛋白质组学和 RNA代谢，以确定每个复合体中与神经退行性变相关的关键蛋白质， 然后通过实验测试这些蛋白质/基因的作用。在整个提案中，我们将使用 无偏见的研究(例如蛋白质组和RNAseq)与系统生物学算法相结合 对上下文相关信息流进行建模，以确定关键的分子相互作用和途径 调节病理、神经退变和神经保护。目标1将确定RBP是否 TIA1指导着MAPT聚集的生化和功能特性。我们发现， 降低RBP TIA1可延缓PS19 P301S MAPT小鼠的疾病进展，尽管产生更多 聚合。我们将阐明TIA1减少产生神经保护的机制 既使用体外分子研究，又使用无偏见的“组学”研究(质谱学和 RNAseq)。我们将应用系统生物学算法来量化关键基因-基因相互作用和 路径，并找出那些与人类状况相似的路径。目标2将决定如何 MAPT和RBP复合体随着人类认知能力的下降而变化。我们将使用质谱学和 RNAseq以确定MAPT、TIA1和其他关键限制性商业惯例的络合物的组成如何变化 在表现为神经炎斑块和神经原纤维缠结的人类病例中，有或没有认知 拒绝。目标3将确定限制性商业惯例是否指导MAPT的菌株以及由此产生的病理 在体外和体内繁殖。我们将描述MAPT的互变传播的特征 来自PS19，PS19xTIA1+/-小鼠的聚集体，以及表现出MAPT病理的人类病例 而且没有认知能力下降。所产生的小鼠将按照目标1中所述进行分析。

Neuritic plaques and neurofibrillary tangles are the hallmark pathologies of Alzheimer's disease (AD), but the presence individual tangles or plaques is not sufficient to predict degeneration; 45% of the elderly with plaques and tangles lack cognitive loss or dementia. We have recently identified a new type of molecular pathology in AD that derives from the aggregation of RNA binding proteins (RBPs), forming RNA-protein complexes, which are termed RNA granules. Microtubule associated protein tau (MAPT) binds to RBPs, co-localizes with RBPs in RNA granules, and RBPs increase MAPT misfolding /aggregation. Importantly, reducing the RBP TIA1 delays progression of tauopathy, despite increased MAPT aggregation. We hypothesize that variation in the composition of MAPT complexes (soluble or insoluble) and RNA granule complexes represent critical determinants of the molecular heterogeneity of AD and other tauopathies, and identify particular pathways that uniquely contribute to each type of disease. We will apply systems biology approaches that integrate information from proteomics and RNA metabolism to identify key proteins in each complex that are associated with neurodegeneration, and then test the roles of these proteins/genes experimentally. Throughout this proposal we will use unbiased studies (e.g., proteomic and RNAseq) combined with the systems biology algorithms to model context-dependent information flows to identify key molecular interactions and pathways regulating pathology, neurodegeneration and neuroprotection. Aim 1 will determine whether the RBP TIA1 directs the biochemical and functional properties of MAPT aggregation. We have discovered that reducing the RBP TIA1 delays disease progression in PS19 P301S MAPT mice despite producing more aggregation. We will elucidate the mechanisms by which TIA1 reduction produces neuroprotection using both in vitro molecular studies, and use unbiased “omic” studies (mass spectrometry and RNAseq). We will apply the systems biology algorithms to quantify key gene-gene interactions and pathways, and identify those pathways that parallel the human condition. Aim 2 will determine how MAPT and RBP complexes vary with cognitive decline in humans. We will use mass spectrometry and RNAseq to determine how the composition of complexes of MAPT, TIA1 and other key RBPs varies among human cases exhibiting neuritic plaques and neurofibrillary tangles with or without cognitive decline. Aim 3 will determine whether RBPs direct the strain of MAPT and resulting pathologies that are propagated in vitro and in vivo. We will characterize propagation of tauopathy for MAPT aggregates from PS19, PS19xTIA1+/--mice, as well as human cases exhibiting MAPT pathology with and without cognitive decline. The resulting mice will be analyzed as described in Aim 1.