Atomic structure of a toxic, oligomeric segment of SOD1 linked to amyotrophic lateral sclerosis (ALS)

Proc Natl Acad Sci U S A. 2017 Aug 15;114(33):8770-8775. doi: 10.1073/pnas.1705091114. Epub 2017 Jul 31.


Fibrils and oligomers are the aggregated protein agents of neuronal dysfunction in ALS diseases. Whereas we now know much about fibril architecture, atomic structures of disease-related oligomers have eluded determination. Here, we determine the corkscrew-like structure of a cytotoxic segment of superoxide dismutase 1 (SOD1) in its oligomeric state. Mutations that prevent formation of this structure eliminate cytotoxicity of the segment in isolation as well as cytotoxicity of the ALS-linked mutants of SOD1 in primary motor neurons and in a Danio rerio (zebrafish) model of ALS. Cytotoxicity assays suggest that toxicity is a property of soluble oligomers, and not large insoluble aggregates. Our work adds to evidence that the toxic oligomeric entities in protein aggregation diseases contain antiparallel, out-of-register β-sheet structures and identifies a target for structure-based therapeutics in ALS.

Keywords: ALS; SOD1; oligomer.

Publication types

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

MeSH terms

  • Amyotrophic Lateral Sclerosis / genetics
  • Amyotrophic Lateral Sclerosis / metabolism*
  • Animals
  • Crystallography, X-Ray / methods
  • Mice
  • Motor Neurons / metabolism
  • Mutation / genetics
  • Protein Conformation, beta-Strand
  • Superoxide Dismutase-1 / genetics
  • Superoxide Dismutase-1 / metabolism*


  • Superoxide Dismutase-1

Associated data

  • PDB/5DLI
  • PDB/5IIW