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.