Nonnative SOD1 trimer is toxic to motor neurons in a model of amyotrophic lateral sclerosis
Open accessAbstract
Significance: Protein aggregation is a hallmark of neurodegenerative disease and is hypothesized to cause neuron death. Despite extensive study of disease-associated aggregating proteins, mechanisms of neuron death remain a mystery, and no cures or effective treatments yet exist. Here, we demonstrate the toxicity of a small aggregate of the Cu,Zn superoxide dismutase (SOD1) protein, associated with amyotrophic lateral sclerosis (ALS). We present an experimentally verified structural model of this toxic species and show that SOD1 mutants designed to promote formation of this aggregate increase cell death, providing a direct link between aggregate presence and neuron death. Knowledge of toxic species and the ability to manipulate their formation provides a valuable direction for pursuit of therapeutic strategies in ALS.
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Mutated SOD1 can form intracellular aggregates in a trimeric form that interfere with motor neuron survival.
“Mutated SOD1 can form intracellular aggregates in a trimeric form that interfere with motor neuron survival (485).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [485]
Cites
The Complex Molecular Biology of Amyotrophic Lateral Sclerosis (ALS)
Redler, R. L., & Dokholyan, N. V. (2012) · Progress in Molecular Biology and Translational Science · doi:10.1016/b978-0-12-385883-2.00002-3 · Cited by 172 · see citing works
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Blood-Brain Barrier: From Physiology to Disease and Back
Sweeney, M. D., Zhao, Z., Montagne, A., Nelson, A. R., & Zlokovic, B. V. (2019) · Physiological Reviews · doi:10.1152/physrev.00050.2017 · Cited by 2,294 · see citing works
- Authors
- Proctor, E. A., Fee, L., Tao, Y., Redler, R. L., Fay, J. M., Zhang, Y., Lv, Z., Mercer, I. P., Deshmukh, M., Lyubchenko, Y. L., & Dokholyan, N. V.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- University of Nebraska Medical Center (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2015-12-30
- Volume
- 113
- Issue
- 3
- Pages
- 614-619
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4725519
- OpenAlex
- W2221151760
- Cited by
- 131
- References
- 1
- Citations by year
- 2026: 8 · 2025: 7 · 2024: 11 · 2023: 8 · 2022: 17 · 2021: 15 · 2020: 10 · 2019: 22 · 2018: 16 · 2017: 10 · 2016: 7
- FWCI
- 7.76
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- HHS | NIH | National Institute of General Medical Sciences (R01GM080742, R01GM096039, R01G078366)
- HHS | NIH | National Institute on Aging (F31AG039266)
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- amyotrophic lateral sclerosis, SOD1, superoxide dismutase 1, protein aggregation, motor neuron degeneration, cytotoxicity, protein misfolding, aggregation intermediates, structural modeling, mutant SOD1, protein stability
- MeSH terms
- Amyotrophic Lateral Sclerosis, Animals, Cell Line, Enzyme Stability, Humans, Models, Biological, Models, Molecular, Motor Neurons, Mutation, Protein Conformation, Superoxide Dismutase, Cell Death, Protein Folding, Mutant Proteins, Protein Multimerization, Protein Aggregates
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