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
Citation
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. (2017) Atomic structure of a toxic, oligomeric segment of SOD1 linked to amyotrophic lateral sclerosis (ALS). Proceedings of the National Academy of Sciences of the United States of America. 114(33):8770-8775.
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
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping