Abstract: α-synuclein (α-syn) aggregation results in the formation of amyloid fibril accumulation in Lewy bodies and Lewy neurites resulting in neurodegenerative diseases such as Parkinson’s disease (PD). Posttranslational modifications, such as phosphorylation, are correlated to the abnormal aggregation of α-syn, however the direct relation between the pathology of α-syn and posttranslational modifications, i.e., phosphorylation, is unknown. α-syn fibrils were synthesized using chemical synthesis in tandem with bacterial expression to generate a site-specific fibril with phosphorylation occurring at Y39. These pY39 fibrils resulted in exacerbated neuronal pathology in rat primary cortical neurons, and reduced clearance of the α-syn fibrils via protease and trypsin digestions. The structure of the pY39 α-syn fibril was determined via cryogenic-electron microscopy (cryo-EM) demonstrating various morphologies and a large electrostatic fibril core surrounding pY39. This work further elucidates the role that phosphorylation has in modulating α-syn pathology, and the morphology of fibrils present in PD.
Originally published at chemistry.nd.edu.