Abstract
ABSTRACTProgressive supranuclear palsy (PSP) is a neurodegenerative disorder that is often misdiagnosed as Parkinson’s Disease (PD) because of shared symptoms. PSP is characterized by the accumulation of tau protein in specific brain regions, which results in loss of balance, gaze impairment, and dementia. Diagnosing PSP is often challenging, and there’s a significant demand for reliable biomarkers. However, existing biomarkers, including tau protein and neurofilament light chain (NfL) levels in cerebrospinal fluid (CSF), show inconsistencies in distinguishing PSP from other neurodegenerative disorders. To overcome these limitations, we conducted a comprehensive proteome analysis for CSF samples from 40 PSP, 40 PD, and healthy controls (HC) using the tandem mass tag-based quantification method, identifying 3,653 unique proteins. Our statistical analysis identified 190, 152, and 247 differentially expressed proteins when comparing PSP vs. HC, PSP vs. PD, and PSP against both PD and HC, respectively. Gene set enrichment analysis and interactome analysis conducted with the differentially expressed proteins in PSP CSF indicated that most of them were implicated in cell adhesion, cholesterol metabolism, and glycan biosynthesis. Cell-type enrichment analysis revealed that neuronally-derived proteins were predominant among the differentially expressed proteins. Potential biomarker classification performance showed 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. This is the first large-scale mass spectrometry-based proteome analysis to discover CSF PSP biomarkers differentiating from both controls and PD, thereby laying a foundation for further development and validation.
Publisher
Cold Spring Harbor Laboratory