Tear proteomics reveals reproducible pathway-level signatures of Parkinson’s disease pathogenesis

Tear fluid is a promising minimally invasive biofluid for studying molecular alterations in neurodegenerative diseases. In this exploratory study, we applied a quantitative dia-PASEF nanoLC-MS/MS workflow to profile the tear proteome in idiopathic Parkinson’s disease (iPD), LRRK2 -associated Parkinson’s disease ( LRRK2 -PD), and healthy controls. Protein identification and quantification were performed using DIA-NN, and statistical analyses were conducted on log₂-transformed data with false discovery rate (FDR) correction using the Storey–Tibshirani method. Tear samples from 77 iPD patients, 7 symptomatic LRRK2 mutation carriers and 86 controls were analysed. iPD showed a broad proteomic shift, with 300 proteins significant after FDR correction and five combining FDR-adjusted significance with large effect sizes. Cross-study comparison with our pilot cohort identified eight concordantly increased proteins significant in both datasets. Exploratory enrichment analysis suggested involvement of epithelial and mucosal homeostasis, innate immunity, cytoskeletal organization, mitochondrial metabolism and endoplasmic reticulum proteostasis. Selected proteins, including MUC5AC, ATPA, KRT19, LCN2 and RARRES1, showed exploratory associations with motor severity and Hoehn and Yahr staging. LRRK2 -PD showed nominal changes only. Overall, these findings identify a restricted set of recurrent tear protein candidates in iPD and support further targeted assessment in larger, clinically and genetically stratified cohorts.