Cerebrospinal Fluid Proteome Reveals Dysregulation of Lysosomal and Axonal Proteins in Neurosyphilis

Neurosyphilis (NS), caused by Treponema pallidum, results in irreversible neurological damage. This study elucidated NS pathogenesis via cerebrospinal fluid (CSF) proteomic analysis comparing NS, suspected neurosyphilis (spNS), and non-neurosyphilis (nNS) controls by using liquid chromatography-tandem mass spectrometry (LC-MS/MS), public data set PXD033034, and ELISA validation. Of 1261 quantified proteins in the CSF, 234 were differentially expressed in NS, with 189 downregulated and enriched in lysosomal, axon guidance, and neurodegeneration pathways. Three previously identified CSF biomarkers of neurosyphilis, i.e., SEMA7A, SERPINA3, and ITIH4, were replicated. Key proteins in the lysosome pathway, including PSAP, CTSL, NPC2, and DNASE2, were significantly downregulated in the CSF of NS patients, and spNS patients presented a high CSF IgG index (spNS-hi-IgG-i). We also identified EPHA4, a key protein in the axon guidance pathway, as significantly downregulated in the CSF of NS patients. A positive correlation between PSAP and EPHA4 suggested a potential impact of lysosomal function on axonostasis in NS. ROC analysis revealed PSAP and DNASE2 as potential biomarkers for assessing neurodegeneration in NS and spNS-hi-IgG-i. These findings suggest that disruptions in lysosomal and axonal processes may contribute to neurodegeneration in NS, and the identified biomarkers hold potential as diagnostic indicators and therapeutic targets.