Elevated erythrocyte membrane pS42-α-synuclein in Parkinson's disease and its changes following plasma...

Blood biomarkers for pathological α-synuclein in Parkinson's disease (PD) are confounded by hemolysis and hemoglobin. Erythrocyte membrane-bound α-synuclein may overcome these challenges.

To investigate whether erythrocyte membrane-bound α-synuclein is altered in PD and whether it changes following plasma cross-incubation.

Erythrocyte membranes from patients with PD and healthy controls were isolated and analyzed by phosphoproteomics to identify phosphorylation sites. Digital western blotting was used for targeted quantification of α-synuclein species. Plasma cross-incubation was performed in a subset of participants.

Phosphorylation patterns of erythrocyte membrane-associated α-synuclein differed between PD and controls. Several phosphorylation sites were detected. Among them, serine 42 (pS42-α-syn) showed the strongest signal and was selected for further analysis. pS42-α-syn levels were higher in PD than in controls (median 0.055 vs. 0.007, P < 0.0001). After plasma cross-incubation, pS42-α-syn levels decreased in both groups. The median percentage reduction was numerically greater in PD than in controls (49.88% vs. 27.44%), although the between-group difference did not reach statistical significance (P = 0.052). Changes in total α-synuclein did not reach statistical significance after plasma cross-incubation (P = 0.23 in controls and P = 0.08 in PD patients). Receiver operating characteristic (ROC) analysis showed good discriminative performance.

Erythrocyte membrane pS42-α-syn is increased in PD. These findings support erythrocyte membrane pS42-α-syn as a peripheral phospho-α-synuclein signal associated with PD.