Neurology

Cell culture studies suggest activating NFE2L2 could help treat ALS by promoting normal folding of mutant SOD1. Crystallographic analyses of an ALS-associated SOD1 mutant complexed with a library of cysteine-reactive compounds identified the NFE2L2 activator ebselen and an ebselen analog that covalently bound the mutant SOD1 at C111 in the groove within the SOD1 homodimer, and in HEK cells the compounds promoted the formation of the disulfide bond required for SOD1 monomers to dimerize. In HEK cells expressing two ALS-associated SOD1 mutants, ebselen increased levels of SOD1 homodimers that folded normally compared with no treatment. Next steps include developing ebselen analogs that promote normal SOD1 folding and testing them in transgenic mouse models of ALS...