Year: 2021
Type: preprint
Abstract: Mutations in the gene encoding Cu-Zn superoxide dismutase 1 (SOD1) cause a subset of familial amyotrophic lateral sclerosis (fALS). One effect of these mutations is that SOD1, which is normally a stable dimer, dissociates into toxic monomers. Considerable research efforts have been devoted to developing compounds that stabilize the dimer of fALS SOD1 variants, but these have not yet resulted in an approved drug. We demonstrate that a cyclic thiosulfinate cross-linker can stabilize prevalent disease-causing SOD1 variants. The degree of stabilization afforded by cyclic thiosulfinates (up to 24 °C) is unprecedented. We show this compound works rapidly in vivo with a half-life of ~3 days. The efficacy, low toxicity, and pharmacodynamics of cross-linker mediated stabilization make it a promising therapeutic approach for SOD1-related fALS. Significance statement Cyclic thiosulfinate S -XL6 enables the kinetic stabilization of ALS-associated SOD1 variants, in vivo.
Authors: Md Amin Hossain, Richa Sarin, Daniel P. Donnelly, Brandon C. Miller, Joseph P. Salisbury, Jeremy B. Conway, Samantha Watson, Jenifer N. Winters, Novera Alam, Durgalakshmi Sivasankar, Aparna C. Ponmudiyan, Tanvi Gawde, Sunanda Kannapadi, Jared R. Auclair, Lee Makowski, Gregory A. Petsko, Dagmar Ringe, David J. Greenblatt, Mary Jo Ondrechen, Yunqiu Chen, Roman Manetsch, Jeffrey N. Agar
Language: English
Subfield: Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funder: National Science Foundation
OpenAlex ID: W3174585728