Post-translational modifications of soluble α-synuclein regulate the amplification of pathological α-synuclein. Academic Article uri icon

Overview

abstract

  • 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 α-synuclein (α-Syn) at previously identified sites dramatically affects the amplification of pathological α-Syn, which underlies Parkinson's disease and other α-synucleinopathies, in a conformation- and phosphorylation site-specific manner. We performed LC-MS/MS analyses on soluble α-Syn purified from Parkinson's disease and other α-synucleinopathies, identifying many new α-Syn post-translational modifications (PTMs). In addition to phosphorylation, acetylation of soluble α-Syn also modified pathological α-Syn transmission in a site- and conformation-specific manner. Moreover, phosphorylation of soluble α-Syn could modulate the seeding properties of pathological α-Syn. Our study represents the first systematic analysis how of soluble α-Syn PTMs affect the spreading and amplification of pathological α-Syn, which may affect disease progression.

publication date

  • January 23, 2023

Research

keywords

  • Neurodegenerative Diseases
  • Parkinson Disease
  • Synucleinopathies

Identity

PubMed Central ID

  • PMC10103650

Scopus Document Identifier

  • 85146637444

Digital Object Identifier (DOI)

  • 10.1038/s41593-022-01239-7

PubMed ID

  • 36690898

Additional Document Info

volume

  • 26

issue

  • 2