PUBLICATION

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

Authors
Sangwan, S., Zhao, A., Adams, K.L., Jayson, C.K., Sawaya, M.R., Guenther, E.L., Pan, A.C., Ngo, J., Moore, D.M., Soriaga, A.B., Do, T.D., Goldschmidt, L., Nelson, R., Bowers, M.T., Koehler, C.M., Shaw, D.E., Novitch, B.G., Eisenberg, D.S.
ID
ZDB-PUB-170802-11
Date
2017
Source
Proceedings of the National Academy of Sciences of the United States of America   114(33): 8770-8775 (Journal)
Registered Authors
Koehler, Carla
Keywords
ALS, SOD1, oligomer
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*
PubMed
28760994 Full text @ Proc. Natl. Acad. Sci. USA
Abstract
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.
Genes / Markers
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Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
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Mapping