Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease that affects more than 20,000 people each year in the United States. Although most cases are sporadic and have no known cause, there is still a significant percentage of cases that have a genetic link. Specifically, there are over 180 different mutations in the gene encoding Cu, Zn superoxide dismutase (SOD1) that causes approximately 7% of all ALS cases in the US. In addition, post-translationally modified (PTM) wild-type SOD1 is associated with as much as 50% of sporadic ALS cases. SOD1 is normally a homodimer, but PTM and ALS-associated mutations have been shown to cause the dimer to dissociate into monomers, which leads to aggregated species. In recent years, research efforts have been made to try to stabilize the SOD1 dimer as a therapeutic strategy. We have recently shown that cyclic disulfide compounds have promise in stabilizing the dimer form of the protein. These compounds form disulfide bonds between the Cys111 residues, located in the dimer interface, of the two subunits of SOD1, and thus tether the two subunits together. Our work uses computational tools to design optimal compounds, with the correct chemical and geometric properties, that may stabilize the dimers of wild-type and ALS-disease associated variants. The best compounds are being synthesized and assayed in the Manetsch and Agar laboratories.

Cyclic disulfide compounds stabilize SOD1 dimers

256th National Meeting (2018)

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