Stabilizing Mutant SOD1 Prevents Aggregation, Improves Cell Survival

Over 100 ALS-associated mutations in superoxide dismutase 1 (SOD1) have been identified, the majority of which yield a destabilized protein product with a propensity to form neurotoxic protein aggregates. Researchers led by Nikolay Dokholyan of the University of North Carolina, Chapel Hill, have developed an approach to mutate SOD1 and prevent its aggregation. As reported online in the September 17 Structure, mutations that mimicked a physiological modification to SOD1, T2-phosphorylation, helped stabilize the SOD1 protein. This modification precluded it from forming aggregates even in the presence of ALS-associated mutations and improved motor neuron survival in cell-based assays. These findings point to a possible new therapeutic approach for the ALS caused by mutations in SOD1.

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Primary Reference:

Fay JM, Zhu C, Proctor EA, Tao Y, Cui W, Ke H, Dokholyan NV. A Phosphomimetic Mutation Stabilizes SOD1 and Rescues Cell Viability in the Context of an ALS-Associated Mutation. Structure. 2016 Sep 17. Epub ahead of print. [Pubmed]

disease-als SOD1 topic-preclinical
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