Linking Thrombin to α-Synuclein truncation reveals a molecular bridge between neuroinflammation and Parkinson disease

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Abstract Proteolytic processing of α-Synuclein (Syn) contributes to the molecular diversity and toxicity of its aggregates in Parkinson disease (PD), yet the proteases responsible for generating disease-relevant truncations remain incompletely defined. Here, we identify thrombin (Thb) — a serine protease best known for its role in haemostasis — as a highly selective Syn-processing enzyme with relevance to neuroinflammatory conditions. Thb predominantly cleaves Syn at Lys6–Gly7, producing a 7–140 fragment as the major proteolytic species. This reaction displays remarkable site specificity despite multiple lysine residues and is modulated by ionic strength and Syn conformational flexibility. The 7–140 fragment adopts a slightly more compact conformational ensemble, shows reduced membrane binding, and forms fibrils with slower aggregation kinetics and altered morphology compared to the full-length protein. These properties may extend the lifetime of soluble oligomeric intermediates, potentially contributing to chronic Syn-mediated toxicity. Our findings reveal a previously unrecognized link between inflammatory Thb activity and Syn proteostasis, suggesting that neuroinflammation-associated proteases may influence PD progression through selective truncation of Syn.

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