Jang Yura, Oh Sungtaek, Hall Anna J, Zhang Zhen, Tropea Thomas F, Chen-Plotkin Alice, Rosenthal Liana S, Dawson Ted M, Na Chan Hyun, Pantelyat Alexander Y
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Clin Proteomics. 2024 Sep 28;21(1):56. doi: 10.1186/s12014-024-09507-3.
Progressive supranuclear palsy (PSP) is a neurodegenerative disorder often misdiagnosed as Parkinson's Disease (PD) due to shared symptoms. PSP is characterized by the accumulation of tau protein in specific brain regions, leading to loss of balance, gaze impairment, and dementia. Diagnosing PSP is challenging, and there is a significant demand for reliable biomarkers. Existing biomarkers, including tau protein and neurofilament light chain (NfL) levels in cerebrospinal fluid (CSF), show inconsistencies in distinguishing PSP from other neurodegenerative disorders. Therefore, the development of new biomarkers for PSP is imperative.
We conducted an extensive proteome analysis of CSF samples from 40 PSP patients, 40 PD patients, and 40 healthy controls (HC) using tandem mass tag-based quantification. Mass spectrometry analysis of 120 CSF samples was performed across 13 batches of 11-plex TMT experiments, with data normalization to reduce batch effects. Pathway, interactome, cell-type-specific enrichment, and bootstrap receiver operating characteristic analyses were performed to identify key candidate biomarkers.
We identified a total of 3,653 unique proteins. Our analysis revealed 190, 152, and 247 differentially expressed proteins in comparisons of PSP vs. HC, PSP vs. PD, and PSP vs. both PD and HC, respectively. Gene set enrichment and interactome analysis of the differentially expressed proteins in PSP CSF showed their involvement in cell adhesion, cholesterol metabolism, and glycan biosynthesis. Cell-type enrichment analysis indicated a predominance of neuronally-derived proteins among the differentially expressed proteins. The potential biomarker classification performance demonstrated that ATP6AP2 (reduced in PSP) had the highest AUC (0.922), followed by NEFM, EFEMP2, LAMP2, CHST12, FAT2, B4GALT1, LCAT, CBLN3, FSTL5, ATP6AP1, and GGH.
Biomarker candidate proteins ATP6AP2, NEFM, and CHI3L1 were identified as key differentiators of PSP from the other groups. This study represents the first large-scale use of mass spectrometry-based proteome analysis to identify cerebrospinal fluid (CSF) biomarkers specific to progressive supranuclear palsy (PSP) that can differentiate it from Parkinson's disease (PD) and healthy controls. Our findings lay a crucial foundation for the development and validation of reliable biomarkers, which will enhance diagnostic accuracy and facilitate early detection of PSP.
进行性核上性麻痹（PSP）是一种神经退行性疾病，由于症状相似，常被误诊为帕金森病（PD）。PSP的特征是特定脑区tau蛋白的积累，导致平衡丧失、凝视障碍和痴呆。诊断PSP具有挑战性，对可靠的生物标志物有很大需求。现有的生物标志物，包括脑脊液（CSF）中的tau蛋白和神经丝轻链（NfL）水平，在区分PSP与其他神经退行性疾病时存在不一致性。因此，开发用于PSP的新生物标志物势在必行。
我们使用基于串联质量标签的定量方法，对40例PSP患者、40例PD患者和40例健康对照（HC）的脑脊液样本进行了广泛的蛋白质组分析。在13批次的11重串联质谱标签（TMT）实验中对120份脑脊液样本进行了质谱分析，并进行数据归一化以减少批次效应。进行了通路、相互作用组、细胞类型特异性富集和自助式受试者工作特征分析，以确定关键的候选生物标志物。
我们共鉴定出3653种独特的蛋白质。我们的分析显示，在PSP与HC、PSP与PD以及PSP与PD和HC的比较中，分别有190、152和247种差异表达蛋白。对PSP脑脊液中差异表达蛋白的基因集富集和相互作用组分析表明，它们参与细胞粘附、胆固醇代谢和聚糖生物合成。细胞类型富集分析表明，差异表达蛋白中神经元来源的蛋白占主导。潜在生物标志物的分类性能表明，ATP6AP2（在PSP中降低）的曲线下面积（AUC）最高（0.922），其次是NEFM、EFEMP2、LAMP2、CHST12、FAT2、B4GALT1、LCAT、CBLN3、FSTL5、ATP6AP1和GGH。
生物标志物候选蛋白ATP6AP2、NEFM和CHI3L1被确定为PSP与其他组的关键鉴别指标。本研究首次大规模使用基于质谱的蛋白质组分析来鉴定进行性核上性麻痹（PSP）特有的脑脊液（CSF）生物标志物，这些生物标志物可将PSP与帕金森病（PD）和健康对照区分开来。我们的发现为可靠生物标志物的开发和验证奠定了关键基础，这将提高诊断准确性并促进PSP的早期检测。
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