Selective interactome vulnerability across the Alzheimer’s disease spectrum

摘要 我们的申请提出识别大脑区域和细胞群中的相互作用组网络漏洞， 在阿尔茨海默病（AD）中选择性失调。目标是在AD频谱中发现 这种选择性脆弱性背后的机制。获得对interactome的系统级见解 功能障碍，我们建议利用我们在应激生物学中的发现， 对称为epichaperomes的长寿命寡聚支架和新型“组学”形成的干扰 该平台称为伴侣组学，提供关于相互作用组网络变化的直接信息。我们的初步 研究表明epichaperomes改变了数千种蛋白质相互作用的方式，并对相互作用组产生了负面影响。 神经网络对神经元功能很重要，包括突触可塑性，细胞间通讯，蛋白质 翻译，细胞周期重新进入，轴突指导，代谢过程和炎症，导致网络范围的 功能障碍和认知能力下降。转基因小鼠和iPSC衍生神经元定位epichaperome的研究 形成作为一个事件，对细胞功能产生负面影响，从疾病过程的早期和整个 疾病进展。在转基因小鼠和AD患者中的研究表明，在AD中形成epichaperome 脆弱的大脑区域这些研究使我们能够假设epichaperomes的积累， 几十年来，epichaperome介导的相互作用组网络失衡，不仅导致内部缺陷， 内在神经元蛋白和蛋白通路，但也在细胞间，在那里它破坏内在网络 细胞和大脑回路的连接。我们保护脆弱的神经元和大脑区域（例如，海马和 默认模式网络的区域）具有更高的积累epichaperomes的倾向，并且反过来 epichaperome介导的功能障碍，由于其内在的解剖学和生物化学。根据PAR-19 - 070， 我们打算在临床和神经病理学特征良好的死后组织中检验这些假设。 人类的大脑我们的目的是研究epichaperome形成的区域和时间轨迹（目的1） 并确定epichaperome形成对AD中选择性脆弱的大脑区域的负面影响 (Aim 2）。我们还计划探索最受这种新发现的病理性疾病影响的神经细胞群。 机制（目标3）。结果是对epichaperomes时空分布的首次洞察 在整个AD谱及其与临床，病理和遗传脆弱性的关系。结果是 也蛋白质组范围内的见解相互作用网络的脆弱性和功能障碍，无论是在他们的性质， 在脆弱的大脑区域的轨迹。来自互动组网络研究的原始数据集和数据分析将被 存放在自由访问的门户网站上，供科学界挖掘和假设生成访问。一 将设计网上用户界面，以便利数据处理和可视化。除了定义 在技术上具有挑战性的见解，相互作用的功能障碍和脆弱性，创新包括两个 诊断和治疗，因为epichaperome介导的脆弱性是有针对性和可成像的。

ABSTRACT Our application proposes to identify interactome network vulnerabilities in brain regions and cell populations that are selectively dysregulated in Alzheimer's disease (AD). The goals are to discover across the AD spectrum the mechanisms underlying such selective vulnerability. To gain systems level insights into interactome dysfunctions, we propose to make use of our discoveries in stress biology linking interactome network perturbations to the formation of long-lived oligomeric scaffolds termed epichaperomes, and of a novel `omics platform called chaperomics that provides direct information on interactome network changes. Our preliminary studies show epichaperomes change how thousands of proteins interact and negatively impact interactome networks important for neuronal function, including synaptic plasticity, cell-to-cell communication, protein translation, cell cycle re-entry, axon guidance, metabolic processes and inflammation, leading to network-wide dysfunction and cognitive decline. Studies in transgenic mice and iPSC-derived neurons position epichaperome formation as an event that negatively impacts cellular function, from early in the disease process and throughout disease progression. Studies in transgenic mice and AD patients suggest epichaperome formation within AD vulnerable brain regions. These studies enable us to hypothesize accumulation of epichaperomes, and in turn of epichaperome-mediated interactome network imbalances, over decades, not only results in defects within intrinsic neuronal proteins and protein pathways but also intercellularly, where it disrupts intrinsic network connectivity of cells and of brain circuits. We posit vulnerable neurons and brain regions (e.g., hippocampus and regions of the default mode network) have a higher propensity to accumulate epichaperomes, and in turn epichaperome-mediated dysfunctions, due to their intrinsic anatomy and biochemistry. In line with PAR-19-070, we intend to test these hypotheses within clinically and neuropathologically well-characterized postmortem human brains. We aim to investigate the regional and temporal trajectory of epichaperome formation (Aim 1) and to determine the negative impact of epichaperome formation on brain regions selectively vulnerable in AD (Aim 2). We also plan to explore neural cell populations most affected by this newly recognized pathologic mechanism (Aim 3). Outcomes are first-of-a-kind insights into the spatio-temporal distribution of epichaperomes across the AD spectrum and their relationship to clinical, pathologic and genetic vulnerabilities. Outcomes are also proteome-wide insights into interactome networks' vulnerabilities and dysfunctions, both on their nature and trajectory in vulnerable brain regions. Raw datasets and data analytics from interactome network studies will be deposited into free-access portals for mining and hypothesis generating access by the scientific community. A web-based user-interface will be designed to facilitate data processing and visualization. In addition to defining technically challenging insights into interactome dysfunctions and vulnerabilities, innovation includes both diagnostics and therapeutics, as epichaperome-mediated vulnerabilities are both targetable and imageable.