To identify plasma protein signatures distinguishing Parkinson’s disease (PD) and multiple system atrophy (MSA), and to evaluate their associations with disease severity and diagnostic potential.

PD and MSA are α-synucleinopathies characterized by progressive neurodegeneration and abnormal protein aggregation. Alterations in plasma protein profiles may mirror underlying pathophysiological processes and provide accessible biomarkers for diagnosis and disease monitoring. Comparative profiling of PD and MSA could yield insights into distinct pathogenic mechanisms and aid differential diagnosis.

We analyzed plasma samples from 69 patients with PD, 38 with MSA, and 69 healthy controls (HC) using the Olink multiplex immunoassay, targeting 92 neurology- and 92 inflammation-related proteins. Age-adjusted ANCOVA, logistic regression, and pathway enrichment analyses were applied to identify disease-associated proteins and signaling pathways.

Thirty-one proteins were elevated in both PD and MSA compared to HC. Seven proteins, including neurofilament light chain (NEFL) and phosphoribosyl transferase domain containing 1 (PRTFDC1), significantly differentiated PD from MSA. A combined NEFL+PRTFDC1 model achieved an AUC of 0.92 for distinguishing PD from MSA. In PD, elevated protein levels correlated negatively with disease duration, suggesting early-stage specificity. Pathway analyses highlighted dysregulation of mTOR and AMPK signaling in both disorders. PD uniquely demonstrated enrichment of HMOX2-associated heme degradation, whereas MSA was characterized by AXIN1-linked WNT/β-catenin signaling.

Multiplex plasma proteomics identified shared dysregulation of mTOR and AMPK pathways in PD and MSA, alongside disease-specific enrichment of HMOX2-mediated heme degradation in PD and AXIN1-driven WNT/β-catenin signaling in MSA. These findings highlight distinct molecular mechanisms underlying PD and MSA and support the diagnostic utility of plasma protein biomarkers.