Solid-state NMR structure of a pathogenic fibril of full-length human α-synuclein

Nat Struct Mol Biol. 2016 May;23(5):409-15. doi: 10.1038/nsmb.3194. Epub 2016 Mar 28.

Abstract

Misfolded α-synuclein amyloid fibrils are the principal components of Lewy bodies and neurites, hallmarks of Parkinson's disease (PD). We present a high-resolution structure of an α-synuclein fibril, in a form that induces robust pathology in primary neuronal culture, determined by solid-state NMR spectroscopy and validated by EM and X-ray fiber diffraction. Over 200 unique long-range distance restraints define a consensus structure with common amyloid features including parallel, in-register β-sheets and hydrophobic-core residues, and with substantial complexity arising from diverse structural features including an intermolecular salt bridge, a glutamine ladder, close backbone interactions involving small residues, and several steric zippers stabilizing a new orthogonal Greek-key topology. These characteristics contribute to the robust propagation of this fibril form, as supported by the structural similarity of early-onset-PD mutants. The structure provides a framework for understanding the interactions of α-synuclein with other proteins and small molecules, to aid in PD diagnosis and treatment.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, N.I.H., Intramural
  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Sequence
  • Amyloid / chemistry*
  • Amyloid / physiology
  • Animals
  • Cells, Cultured
  • Humans
  • Hydrogen Bonding
  • Lewy Bodies / chemistry
  • Mice
  • Neurons / physiology
  • Nuclear Magnetic Resonance, Biomolecular
  • Parkinson Disease / pathology
  • Protein Domains
  • Protein Folding
  • Protein Structure, Quaternary
  • Protein Structure, Secondary
  • alpha-Synuclein / chemistry*
  • alpha-Synuclein / physiology

Substances

  • Amyloid
  • SNCA protein, human
  • alpha-Synuclein