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

摘要 越来越多的证据表明，神经炎症不是神经变性的简单后果 帕金森氏病(PD)，但在疾病进展中是一个活跃的过程。因此，生物标志物能够检测到， 分期和监测这些通路的改变有望显著推进PD治疗。我们 最近开发了一种蛋白质组流水线，利用创新的基于网络的策略来识别 脑脊液生物标记物反映神经退行性疾病以脑为基础的病理生理， 包括炎症和免疫介导的过程。该入路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性的、疾病特异性的脑脊液生物标志物面板 与胶质细胞介导的炎症、内皮体液免疫和髓鞘功能障碍有关。我们假设 同样，帕金森病在脑脊液中具有独特的蛋白质特征，反映了脑部的神经炎症和 免疫介导的退行性变。因此，我们建议利用这一网络蛋白质组学策略来识别和 验证有前景的帕金森病神经炎症的脑脊液生物标志物。目标1将包括无偏见的网络分析 帕金森病脑蛋白质组中局部炎性功能障碍的研究，描绘了与 脆弱区域的免疫调节过程。这一基于网络的分析将有助于解开 帕金森病脑内炎症生物学的复杂性，区分细胞类型(例如，小胶质细胞，星形细胞， 内皮细胞)和功能特性(例如，体液、先天、促炎或抗炎)显著相关 带着疾病。在目标2中，我们将把这些结果与PD-CSF的差异表达分析相结合 蛋白质组，以确定脑脊液生物标记物与这些基于大脑的炎症途径的联系。我们将确定优先顺序 基于PD差异表达的稳健性和重复性的进一步验证的生物标志物，疾病- 帕金森病的特异性、与脑部炎症的关联强度，以及使用高 吞吐量MS策略。未来的方向将包括对这些优先顺序的大规模目标MS验证 生物标记物的首要目标是开发一种PD炎症的多重检测方法，可用于 诊断患者概况、监控疾病进展、个性化治疗策略并确认 毒品目标交战。

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.