α-Synuclein Aggregation Intermediates form Fibril Polymorphs with Distinct Prion-like Properties

J Mol Biol. 2022 Oct 15;434(19):167761. doi: 10.1016/j.jmb.2022.167761. Epub 2022 Jul 27.

Abstract

α-Synuclein (α-Syn) amyloids in synucleinopathies are suggested to be structurally and functionally diverse, reminiscent of prion-like strains. The mechanism of how the aggregation of the same precursor protein results in the formation of fibril polymorphs remains elusive. Here, we demonstrate the structure-function relationship of two polymorphs, pre-matured fibrils (PMFs) and helix-matured fibrils (HMFs), based on α-Syn aggregation intermediates. These polymorphs display the structural differences as demonstrated by solid-state NMR and mass spectrometry studies and also possess different cellular activities such as seeding, internalization, and cell-to-cell transfer of aggregates. HMFs, with a compact core structure, exhibit low seeding potency but readily internalize and transfer from one cell to another. The less structured PMFs lack transcellular transfer ability but induce abundant α-Syn pathology and trigger the formation of aggresomes in cells. Overall, the study highlights that the conformational heterogeneity in the aggregation pathway may lead to fibril polymorphs with distinct prion-like behavior.

Keywords: amyloids; polymorphs; synucleinopathies; α-Synuclein.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid / chemistry
  • Humans
  • Inclusion Bodies / chemistry
  • Magnetic Resonance Spectroscopy
  • Prions* / metabolism
  • Protein Aggregation, Pathological*
  • alpha-Synuclein* / chemistry

Substances

  • Amyloid
  • Prions
  • alpha-Synuclein