C-terminally truncation is a prominent post-translational modification of human erythrocyte α-synuclein

Abstract

Abstract α-Synuclein is a protein related to synucleinopathies with high expression in the central nervous system and erythrocytes which are a major source of peripheral α-synuclein. Recent reports have suggested the presence of α-synuclein within extracellular vesicles derived from erythrocytes, potentially contributing to the pathogenesis of synucleinopathies. While Lewy bodies, intracellular inclusions containing aggregated α-synuclein, are prominently observed within the brain, their occurrence in peripheral neurons implies the dissemination of synucleinopathy pathology throughout the body via the propagation of α-synuclein. In this study, we found erythrocytes and circulating extracellular vesicles obtained from plasma contained α-synuclein, which was separated into four major forms using high-resolution clear native-PAGE and isoelectric focusing. Notably, erythrocyte α-synuclein was classified into full-length and C-terminal truncated forms, with truncation observed between Y133 and Q134 as determined by LC-MS/MS analysis. Our finding revealed that C-terminally truncated α-synuclein, which was previously reported to exist solely within the brain, was also present in erythrocytes and circulating extracellular vesicles obtained from plasma.