The cysteine-reactive small molecule ebselen facilitates effective SOD1 maturation

• DOI: 10.1038/s41467-018-04114-x
• Publication Date: 2018-04-23T11:19:49Z
• Authors: Michael J. Capper; Gareth S. A. Wright; Letizia Barbieri; Enrico Luchinat; Eleonora Mercatelli; Luke McAlary; Justin J. Yerbury; Paul M. O’Neill; Svetlana V. Antonyuk; Lucia Banci; S. Samar Hasnain
• Keywords: Ebselen; Chaperone (clinical); HCCS

Superoxide dismutase-1 (SOD1) mutants, including those with unaltered enzymatic activity, are known to cause amyotrophic lateral sclerosis (ALS). Several destabilizing factors contribute pathogenicity a reduced ability complete the normal maturation process which comprises folding, metal cofactor acquisition, intra-subunit disulphide bond formation and dimerization. Immature SOD1 forms toxic oligomers characteristic large insoluble aggregates within motor system cells. Here we report that cysteine-reactive molecule ebselen efficiently confers directs correct depopulating globally unfolded precursor associated aggregation toxicity. Assisted of unusual cytosolic could have potential therapeutic applications. In less reducing environments, selenylsulphide Cys111 restores monomer-dimer equilibrium A4V wild-type. Ebselen is therefore potent bifunctional pharmacological chaperone for combines properties hCCS recently licenced antioxidant drug, edaravone.