The fold of alpha-synuclein fibrils

Proc Natl Acad Sci U S A. 2008 Jun 24;105(25):8637-42. doi: 10.1073/pnas.0712179105. Epub 2008 Jun 12.

Abstract

The aggregation of proteins into amyloid fibrils is associated with several neurodegenerative diseases. In Parkinson's disease it is believed that the aggregation of alpha-synuclein (alpha-syn) from monomers by intermediates into amyloid fibrils is the toxic disease-causative mechanism. Here, we studied the structure of alpha-syn in its amyloid state by using various biophysical approaches. Quenched hydrogen/deuterium exchange NMR spectroscopy identified five beta-strands within the fibril core comprising residues 35-96 and solid-state NMR data from amyloid fibrils comprising the fibril core residues 30-110 confirmed the presence of beta-sheet secondary structure. The data suggest that beta1-strand interacts with beta2, beta2 with beta3, beta3 with beta4, and beta4 with beta5. High-resolution cryoelectron microscopy revealed the protofilament boundaries of approximately 2 x 3.5 nm. Based on the combination of these data and published structural studies, a fold of alpha-syn in the fibrils is proposed and discussed.

Publication types

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

MeSH terms

  • Amyloid / chemistry*
  • Cryoelectron Microscopy
  • Deuterium Exchange Measurement
  • Microscopy, Electron, Transmission
  • Nuclear Magnetic Resonance, Biomolecular
  • Protein Folding
  • Protein Structure, Secondary
  • alpha-Synuclein / chemistry*

Substances

  • Amyloid
  • alpha-Synuclein