Advancing Proteomics Technologies to Decipher the Ubiquitin-Proteasome System

阿尔茨海默病(AD)是一种不可治愈的与年龄相关的进行性神经退行性疾病。目前， 阿尔茨海默病引起的记忆丧失和认知缺陷的分子机制仍不清楚。系统化 中枢神经系统(CNS)的特征对于了解神经退行性疾病是必不可少的。 然而，由于神经网络的巨大复杂性，对其进行详细分析仍然具有极大的挑战性。 人脑由近千亿个神经元组成，这些神经元相互连接形成一个 极其复杂和精致的神经元电路。虽然目前基于MS的蛋白质组学方法已经 使蛋白质组的全球图谱和人脑中的翻译后修饰成为可能，我们对 与阿尔茨海默病相关的神经元网络的动态和功能组织和调节仍然非常重要 有限的。因此，迫切需要定义与AD相关的分子网络，以促进我们的 对其病理生物学的了解。蛋白质-蛋白质相互作用是蛋白质形成的基础 在调节细胞活动的过程中，对协调一系列不同的途径至关重要。反常的 PPI与AD和其他神经退行性疾病有关，然而，在 阿尔茨海默病发生的蛋白质复合体和网络通路尚未得到很好的研究。因此， 对健康和疾病状态下蛋白质复合体的相互作用情况进行系统范围的描述是至关重要的 更深入地了解神经生物学和神经病理学，并最终发现新的 基于交互作用的诊断和治疗。在本补充资料中，我们建议使用交联体 光谱学(XL-MS)技术分析AD模型大鼠脑组织中蛋白质的相互作用 患者样本，使我们能够第一次解开具有PPI身份和接触地点的神经元网络。 我们新颖的XL-MS技术确定的分子细节无疑将提供独特的见解 不能通过其他方法轻易揭示。结果将使我们能够定义蛋白质模块和网络 从而揭示了阿尔茨海默病的病理生理机制的新的分子细节 广告。

Alzheimer’s disease (AD) is an incurable age-related progressive neurodegenerative disorder. Currently, molecular mechanisms underlying memory loss and cognitive defects caused by AD remain elusive. Systematic characterization of the central nervous system (CNS) is essential to understanding neurodegenerative disorders. However, detailed analysis of neuronal networks remains extremely challenging due to the enormous complexity of the human brain, which is comprised of nearly a hundred billion neurons that interconnect to form an exceedingly intricate and delicate neuronal circuitry. While current MS-based proteomics approaches have enabled global profiling of proteomes and posttranslational modifications in human brains, our understanding of the dynamic and functional organization and regulation of neuronal networks associated with AD remains very limited. Therefore, there is an urgent need to define the molecular networks associated with AD to advance our understanding of its pathobiology. Protein-protein interactions (PPIs) are fundamental to the formation of protein complexes and crucial for orchestrating a diverse array of pathways in regulating cellular activities. Aberrant PPIs have been associated with AD and other neurodegenerative disorders, however, molecular alterations in protein complexes and network pathways specific to AD development have not been well explored. Therefore, systems-wide profiling of interaction landscapes of protein complexes in healthy and diseased states is crucial for a deeper understanding of neurobiology and neuropathology, and ultimately the discovery of novel interaction-based diagnostics and therapeutics. In this supplement, we propose to employ cross-linking mass spectrometry (XL-MS) technologies to dissect protein interaction landscapes in brain tissues of AD models and patient samples to allow us to unravel neuronal networks with PPI identities and contact sites for the first time. The molecular details determined by our novel XL-MS technology will undoubtedly provide unique insights that cannot be easily revealed by other approaches. The results will allow us to define protein modules and networks associated with AD and thus uncover new molecular details underlying the pathophysiological mechanisms of AD.