Proteomics identified carboxypeptidase E as a novel biomarker for synucleinopathies

Aggregated alpha-synuclein (α-syn) forms Lewy bodies (LBs) in neurons in Parkinson’s disease (PD) and glial cytoplasmic inclusions (GCIs) in oligodendrocytes in Multiple System Atrophy (MSA). However, the molecular composition of these inclusions and the molecular features associated with different synucleinopathy-related inclusion types remain incompletely understood. Here, we characterized α-syn-positive inclusion bodies across disease-relevant brain regions using spatial proteomics in postmortem PD and MSA brains. Comparative analysis identified 614 proteins shared between LB and GCI proteomes, including 57 proteins showing differential enrichment between the two inclusion types. Among these, carboxypeptidase E (CPE) exhibited significant co-aggregation with α-syn in both PD and MSA brains. We further quantified serum CPE levels by enzyme-linked immunosorbent assay in a discovery cohort (66 PD, 37 MSA, and 23 non-neurodegenerative controls [NNCs]) and a salivary α-syn real-time quaking-induced conversion (RT-QuIC)—positive cohort (26 PD, 14 MSA, and 22 NNCs). Serum CPE levels were significantly reduced in synucleinopathy patients compared with controls and showed robust diagnostic performance across both cohorts. Lower CPE levels were inversely correlated with selected markers of clinical disease severity. These findings identify CPE as a co-aggregated protein associated with α-syn-positive inclusions and support its further evaluation as a candidate biomarker for synucleinopathies.