Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 114, Issue 33, Pages 8770-8775Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1705091114
Keywords
oligomer; SOD1; ALS
Categories
Funding
- Howard Hughes Medical Institute, Department of Energy
- National Institutes of Health (NIH) [AG029430]
- University of California, Los Angeles (UCLA) Broad Center of Regenerative Medicine and Stem Cell Research
- Rose Hills Foundation
- National Institute of Neurological Disorders and Stroke [NS072804]
- Muscular Dystrophy Association [92901]
- California Institute for Regenerative Medicine (CIRM) [RB1-01367, RB5-07480]
- CIRM [RT307678]
- National Institute of General Medical Sciences [GM61721]
- NIH [AG047116]
- National Science Foundation [CHE-1301032, CHE-1565941]
- Whitcome Pre-Doctoral fellowship
- UCLA Cellular and Molecular Biology Training program (Ruth L. Kirschstein NIH Grant) [GM007185]
- UCLA-California Institute for Regenerative Medicine Training Grant
- UCLA Graduate Division Dissertation Year Fellowship
- Larry L. Hillblom Foundation Fellowship
- Beckman Research Scholarship
- Division Of Chemistry
- Direct For Mathematical & Physical Scien [1301032] Funding Source: National Science Foundation
Ask authors/readers for more resources
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 beta-sheet structures and identifies a target for structurebased therapeutics in ALS.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available