Cryo-EM structure of alpha-synuclein fibrils

Elife. 2018 Jul 3;7:e36402. doi: 10.7554/eLife.36402.

Abstract

Parkinson's disease is a progressive neuropathological disorder that belongs to the class of synucleinopathies, in which the protein alpha-synuclein is found at abnormally high concentrations in affected neurons. Its hallmark are intracellular inclusions called Lewy bodies and Lewy neurites. We here report the structure of cytotoxic alpha-synuclein fibrils (residues 1-121), determined by cryo-electron microscopy at a resolution of 3.4 Å. Two protofilaments form a polar fibril composed of staggered β-strands. The backbone of residues 38 to 95, including the fibril core and the non-amyloid component region, are well resolved in the EM map. Residues 50-57, containing three of the mutation sites associated with familial synucleinopathies, form the interface between the two protofilaments and contribute to fibril stability. A hydrophobic cleft at one end of the fibril may have implications for fibril elongation, and invites for the design of molecules for diagnosis and treatment of synucleinopathies.

Keywords: E. coli; Parkinson's disease; alpha-synuclein; cryo-electron microscopy; fibril; human; molecular biophysics; neurodegeneration; neuroscience; structural biology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Cryoelectron Microscopy*
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Models, Molecular
  • Mutation / genetics
  • Parkinson Disease / genetics
  • alpha-Synuclein / chemistry
  • alpha-Synuclein / ultrastructure*

Substances

  • alpha-Synuclein