Developing Biomarkers of Parkinson’s Disease Inflammation Using a Network Proteomics Approach

摘要 越来越多的证据表明，神经炎症不是神经退行性变的简单结果， 帕金森病（PD），但在疾病进展的一个积极的过程。因此，能够检测， 分期和监测这些通路的变化有望显著推进PD治疗。我们 最近开发了一种蛋白质组学管道，利用创新的基于网络的策略来识别 反映神经退行性疾病中基于脑的病理生理学的脑脊液（CSF）生物标志物， 包括炎症和免疫介导的过程。这种方法在脑和脑脊液中的应用 阿尔茨海默病（AD）的蛋白质组产生了高度可重复的疾病特异性CSF生物标志物组 与神经胶质介导的炎症、内皮体液免疫和髓鞘功能障碍有关。我们假设 PD在CSF中同样具有反映基于脑的神经炎症的独特蛋白质特征， 免疫介导的变性。因此，我们建议利用这种网络蛋白质组学策略来识别和 验证PD神经炎症的有前景的CSF生物标志物。目标1将包括无偏网络分析 PD脑蛋白质组中的局部炎症功能障碍，描绘与PD相关的蛋白质改变。 免疫介导的过程中脆弱的地区。这种基于网络的分析将有助于解开 PD脑中炎症生物学的复杂性，区分细胞类型（例如，小胶质细胞，星形胶质细胞， 内皮）和功能特性（例如，体液性、先天性、促炎性或抗炎性）显著相关 疾病。在目标2中，我们将这些结果与PD CSF的差异表达分析相结合， 蛋白质组来鉴定与这些基于脑的炎症通路相关的CSF生物标志物。我们将优先考虑 基于PD差异表达的稳健性和再现性，疾病- PD的特异性，与脑炎症的关联强度，以及使用高 吞吐量MS策略。未来的方向将包括大规模的有针对性的MS验证这些优先 生物标志物的总体目标是开发一种可用于 对患者进行诊断分析，监测疾病进展，制定个体化治疗策略，并确认 药物靶向接合。

ABSTRACT Increasing evidence indicates that neuroinflammation is not a simple consequence of neurodegeneration in Parkinson’s disease (PD), but an active process in disease progression. Thus, biomarkers capable of detecting, staging, and monitoring alterations in these pathways promise to significantly advance PD therapeutics. We recently developed a proteomic pipeline that leverages innovative network-based strategies to identify panels of cerebrospinal fluid (CSF) biomarkers reflective of brain-based pathophysiology in neurodegenerative disease, including inflammatory and immune-mediated processes. The application of this approach to the brain and CSF proteomes of Alzheimer’s disease (AD) yielded highly reproducible, disease-specific CSF panels of biomarkers linked to glial-mediated inflammation, endothelial humoral immunity, and myelin dysfunction. We hypothesize that PD similarly features unique protein signatures in CSF reflective of brain-based neuroinflammation and immune-mediated degeneration. Thus, we propose to utilize this network proteomics strategy to identify and validate promising CSF biomarkers of PD neuroinflammation. Aim 1 will comprise an unbiased network analysis of regional inflammatory dysfunction in the PD brain proteome, delineating protein alterations linked to immune-mediated processes in vulnerable regions. This network-based analysis will help unravel the complexities of inflammatory biology in the PD brain, distinguishing cell types (e.g., microglial, astrocytic, endothelial) and functional properties (e.g., humoral, innate, pro- or anti-inflammatory) significantly associated with disease. In Aim 2, we will then integrate these results with differential expression analysis of the PD CSF proteome to identify CSF biomarkers with links to these brain-based inflammatory pathways. We will prioritize biomarkers for further validation based on robustness and reproducibility of PD differential expression, disease- specificity for PD, strength of association with brain-based inflammation, and ease of detectability using high- throughput MS strategies. Future directions will include large-scale targeted MS validation of these prioritized biomarkers with the overarching goal of developing a multiplex assay of PD inflammation that can be used to diagnostically profile patients, monitor disease progression, individualize therapeutic strategies, and confirm drug target engagement.