Selective interactome vulnerability across the Alzheimer’s disease spectrum

摘要 阿尔茨海默病（AD）中从细胞到网络的选择性脆弱性机制 谱仍然未知，限制了我们对疾病的了解，阻碍了有效治疗的发展。 治疗我们建议识别脑细胞和区域中的蛋白质-蛋白质相互作用（PPI）网络功能障碍 作为AD中选择性漏洞机制的网关。为了获得系统级的见解，我们建议利用 我们在应激生物学中的发现将相互作用组网络扰动与长寿命 寡聚支架称为epichaperomes，并采用一种新的`组学平台称为epichaperomics， 提供有关PPI网络更改的直接信息。初步研究表明epichaperomes如何改变 数以千计的蛋白质相互作用并对PPI网络产生负面影响，这些网络对神经元功能至关重要，包括 突触可塑性，细胞间通讯，蛋白质翻译，细胞周期再进入，轴突导向，代谢 过程和炎症，导致细胞和连接体功能障碍和认知能力下降。平行 在转基因小鼠和iPSC衍生的神经元中的研究表明epichaperome形成是一个关键事件， 从早期前驱疾病阶段和整个疾病进展对细胞功能产生负面影响。 转基因小鼠和AD死后大脑的初步结果表明， 主要是在脆弱的脑细胞和区域内。因此，我们假设epichaperome形成， 反过来，epichaperome介导的PPI网络失衡，几十年来，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有更高的倾向 积累epichaperomes和epichaperome-mediated功能障碍。根据NOT-AG-21-040， 我们建议揭示个别脑细胞和区域内PPI功能障碍的机制， AD的选择性脆弱性，这仍然是未知的，也是一个关键的缺失部分。我们的目标是i）调查 能够实现（即，epichaperomes，目标1）和ii）那些执行（即，影响蛋白质和 蛋白质通路，目标2）PPI网络中的特定功能障碍。作为联系压力源和 表型，我们的目标是揭示细胞和区域特定的脆弱性PPI网络诱导的个人 压力源（目标3）。结果提供了第一个一类的洞察时空的形成和分布， epichaperomes在整个AD谱及其与临床，病理和遗传脆弱性的关系。 结果是关键的蛋白质组范围的见解相互作用组的脆弱性，无论是在性质和轨迹 脆弱的脑细胞和脑区。原始数据集和数据分析将直接存入 科学界成员可免费访问网站进行挖掘和假设检验。除了定义 在技术上具有挑战性的机械洞察选择性AD漏洞，创新包括诊断和 治疗，因为epichaperome介导的功能障碍是可成像的和可靶向的。

ABSTRACT Mechanisms underlying selective vulnerability from cells to networks across the Alzheimer's disease (AD) spectrum remain unknown, limiting our understanding of disease and hampering development of effective therapies. We propose to identify protein-protein interaction (PPI) network dysfunctions in brain cells and regions as a gateway to selective vulnerability mechanisms in AD. To gain systems level insights, we propose to leverage our discoveries in stress biology linking interactome network perturbations to the formation of long-lived oligomeric scaffolds termed epichaperomes, and to employ a novel `omics platform called epichaperomics that provides direct information on PPI network changes. Preliminary studies indicate epichaperomes change how thousands of proteins interact and negatively impact PPI 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 cell and connectome-wide dysfunction and cognitive decline. Parallel studies in transgenic mice and iPSC-derived neurons demonstrate epichaperome formation is a key event that negatively impacts cellular function, from early prodromal disease stages and throughout disease progression. Preliminary results in transgenic mice and postmortem AD brains suggest epichaperome formation occurs principally within vulnerable brain cells and regions. Accordingly, we hypothesize epichaperome formation, and in turn of epichaperome-mediated PPI 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 have a higher propensity to accumulate epichaperomes, and epichaperome-mediated dysfunctions. In accordance with NOT-AG-21-040, we propose to uncover mechanisms of PPI dysfunctions within individual brain cells and regions as a portal into selective vulnerability in AD, which remains unknown and a key missing piece. We aim to i) investigate mechanisms that enable (i.e., epichaperomes, Aim 1) and ii) those that execute (i.e., impacted proteins and protein pathways, Aim 2) context-specific dysfunctions in PPI networks. As a key element in linking stressors-to- phenotype, we aim to uncover cell- and region-specific vulnerabilities within PPI networks induced by individual stressors (Aim 3). Results provide first-of-a-kind insights into the spatio-temporal formation and distribution of epichaperomes across the AD spectrum and their relationship to clinical, pathologic, and genetic vulnerabilities. Outcomes are critical proteome-wide insights into interactome vulnerabilities, both on the nature and trajectory within vulnerable brain cells and brain regions. Raw datasets and data analytics will be deposited directly into free access sites for mining and hypothesis testing by members of the scientific community. In addition to defining technically challenging mechanistic insights into selective AD vulnerabilities, innovation includes diagnostics and therapeutics, as epichaperome-mediated dysfunctions are both imageable and targetable.