Objective: Employing a proteomics approach, this study aimed to profile immune dysregulation signatures in male and female Parkinson’s disease (PD) patients, as well as in early-onset PD (EOPD) and late-onset PD (LOPD).

Background: Growing evidence has supported the involvement of immunity in initiating and advancing PD.

Method: This study involved 52,778 participants with proteomics data from the UK Biobank (UKB). Immune signatures of PD were profiled by the individual plasma proteins associated with each PD group and the enriched KEGG pathways based on these proteins, and were validated in the Parkinson’s Progression Markers Initiative (PPMI). Correlations between significant proteins and the severity of PD, measured by the UPDRS scores, were further investigated in the PPMI.

Results: Over 13.74 years of follow-up, 797 incident cases of PD were identified in UKB, including 500 male PD and 792 LOPD cases, respectively. Several individual significant plasma proteins, such as ITGAV, TNFRSF9, CCN3 in male PD, ITGAV, ITGAM, ITGB2 in female PD, and ITGAV, ITGAM, SCG2 in LOPD were identified in both cohorts. Pathway analysis revealed a core, shared immune signature, which was centered on immune response, inflammation, and cell adhesion, in both male and female PD patients. Beyond these common pathways, unique signatures included NF-κB signaling and rheumatoid arthritis pathways in males, which were validated and further expanded in the PPMI cohort with T-cell polarization. In females, cell morphology and motility pathways were observed in both cohorts, alongside a cardiovascular and metabolic signature that was also shared but stronger in PPMI. When stratified by age of onset, broad pathways encompassing immunity, infection, and cellular signaling were identified for LOPD in both cohorts. For EOPD, PPMI revealed microglia activation via Toll-like and NOD-like receptor pathways, early blood-brain barrier compromise, autoimmune predisposition via Th17/IL-17 signaling, and features of metabolic inflammation. In PPMI, specific plasma proteins showed significant correlations with motor and non-motor symptom progression, which were distinct across different PD groups.

Conclusion: Our study delineates both shared and distinct immune signatures of PD across sex and age-of-onset subgroups. This layered understanding of common yet divergent pathophysiological mechanisms may inform targeted, subgroup-specific therapeutic strategies.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/proteomics-reveals-sex-and-age-of-onset-stratified-immune-dysregulations-in-parkinsons-disease/