Lysosomal Expression Profile in Plasma Associates with Disease Severity in Parkinson's Disease

BACKGROUND: Parkinson's disease (PD) is a clinically and biologically heterogeneous neurodegenerative disorder, driven by multiple mechanisms among which are lysosomal and mitochondrial dysfunction. Here, we explored blood-based lysosomal and mitochondrial profiles in relation to PD diagnosis and severity. METHODS: Plasma samples (n = 504) were analyzed using SomaScan, targeting 394 lysosomal and 502 mitochondrial proteins in a discovery (ProPARK: 145 PD, 73 controls) and a validation cohort (Alzheimer's Disease Research Center [ADRC]: 104 PD, 182 controls). Linear and LASSO regression were included to compare groups and select PD-predictive proteins. Associations with Unified Parkinson's Disease Rating Scale (UPDRS), Hoehn and Yahr, Montreal Cognitive Assessment (MoCA), levodopa equivalent daily dose (LEDD) and disease duration were assessed and age-, sex-, and false discovery rate (FDR)-adjusted. RESULTS: In ProPARK, 29 dysregulated lysosomal and 46 mitochondrial proteins were identified in PD; upregulated lysosomal sulfatase-modifying factor 1 (SUMF1) (FC = 1.41) and arrestin domain containing 3 (ARRDC3) (1.36) survived correction. LASSO identified eight lysosomal proteins (area under the curve [AUC] train: 0.83, test: 0.75) and two mitochondrial proteins (AUC train: 0.66, test: 0.65). Lysosomal score associated with disease duration, LEDD, and UPDRS-IV, whereas mitochondrial score did not. SUMF1 associated with disease duration, LEDD, and UPDRS-IV; ARRDC3 only with disease duration. In ADRC, upregulation of SUMF1 and ARRDC3 in PD (FC = 1.72 and 1.36), their association with LEDD, discriminatory AUCs of lysosomal and mitochondrial scores (0.80 and 0.58), and the association between lysosomal score and LEDD replicated. CONCLUSIONS: Lysosomal expression scores discriminated PD from controls and associated with disease severity. SUMF1 and ARRDC3 emerged as blood-based biomarkers for PD. These findings support the use of pathway-specific biomarkers for improving PD diagnostics and monitoring disease progression. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.