Post-translational modifications of soluble alpha-synuclein regulate the amplification of pathological alpha-synuclein

Pathological alpha-synuclein (alpha-Syn) spreading is critical for the progression of many neurodegenerative diseases. The authors demonstrate that soluble alpha-Syn post-translational modifications (PTMs) dramatically modulate pathological alpha-synuclein spreading. Cell-to-cell transmission and subsequent amplification of pathological proteins promote neurodegenerative disease progression. Most research on this has focused on pathological protein seeds, but how their normal counterparts, which are converted to pathological forms during transmission, regulate transmission is less understood. Here we show in cultured cells that phosphorylation of soluble, nonpathological alpha-synuclein (alpha-Syn) at previously identified sites dramatically affects the amplification of pathological alpha-Syn, which underlies Parkinson & apos;s disease and other alpha-synucleinopathies, in a conformation- and phosphorylation site-specific manner. We performed LC-MS/MS analyses on soluble alpha-Syn purified from Parkinson & apos;s disease and other alpha-synucleinopathies, identifying many new alpha-Syn post-translational modifications (PTMs). In addition to phosphorylation, acetylation of soluble alpha-Syn also modified pathological alpha-Syn transmission in a site- and conformation-specific manner. Moreover, phosphorylation of soluble alpha-Syn could modulate the seeding properties of pathological alpha-Syn. Our study represents the first systematic analysis how of soluble alpha-Syn PTMs affect the spreading and amplification of pathological alpha-Syn, which may affect disease progression.