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

Sangwan, Smriti; Zhao, Anni; Adams, Katrina L.; Jayson, Christina K.; Sawaya, Michael R.; Guenther, Elizabeth L.; Pan, Albert C.; Ngo, Jennifer; Moore, Destaye M.; Soriaga, Angela B.; Do, Thanh D.; Goldschmidt, Lukasz; Nelson, Rebecca; Bowers, Michael T.; Koehler, Carla M.; Shaw, David E.; Novitch, Bennett G.; Eisenberg, David S.

doi:10.1073/pnas.1705091114

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

Journal Article · Mon Jul 31 00:00:00 EDT 2017 · Proceedings of the National Academy of Sciences of the United States of America

DOI:https://doi.org/10.1073/pnas.1705091114· OSTI ID:1390865

Sangwan, Smriti ^[1]; Zhao, Anni ^[1]; Adams, Katrina L. ^[2]; Jayson, Christina K. ^[1]; Sawaya, Michael R. ^[1]; Guenther, Elizabeth L. ^[1]; Pan, Albert C. ^[3]; Ngo, Jennifer ^[1]; Moore, Destaye M. ^[2]; Soriaga, Angela B. ^[1]; Do, Thanh D. ^[4]; Goldschmidt, Lukasz ^[1]; Nelson, Rebecca ^[1]; Bowers, Michael T. ^[4]; Koehler, Carla M. ^[1]; Shaw, David E. ^[5]; Novitch, Bennett G. ^[2]; Eisenberg, David S. ^[1]

Univ. of California, Los Angeles, CA (United States)
David Geffen School of Medicine at UCLA, Los Angeles, CA (United States)
D. E. Shaw Research, New York, NY (United States)
Univ. of California, Santa Barbara, CA (United States)
D. E. Shaw Research, New York, NY (United States); Columbia Univ., New York, NY (United States)

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 aDanio rerio(zebrafish) model of ALS. Cytotoxicity assays suggest that toxicity is a property of soluble oligomers, and not large insoluble aggregates. Here, 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.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: California Inst. for Regenerative Medicine (CIRM); Muscular Dystrophy Association; National Inst. of General Medical Sciences; National Inst. of Health (NIH); National Inst. of Neurological Disorders and Stroke; National Science Foundation

OSTI ID:: 1390865

Journal Information:: Proceedings of the National Academy of Sciences of the United States of America, Journal Name: Proceedings of the National Academy of Sciences of the United States of America Journal Issue: 33 Vol. 114; ISSN 0027-8424

Publisher:: National Academy of SciencesCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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

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