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

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.

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.

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.

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.