Identification of a Misfolded Region in Superoxide Dismutase 1 that is Exposed in Amyotrophic Lateral Sclerosis

Rotunno MS, 289(41):28527-38, J Biol Chem, 2014

A fatal neurodegenerative disorder called ALS (amyotrophic lateral sclerosis) caused by mutations and post-translational modifications within Cu,Zn-superoxide dismutase (SOD1), is an incurable disease and there are challenges in developing effective therapies due to its complex nature. The C4F6 antibody selectively binds to an epitope on misfolded SOD1 from human and mouse ALS cases. A variety of approaches including chemical cross-linking, mass spectrometry, site-directed mutagenesis, and BLI helped in the current study to obtain a detailed understanding of the structural elements and the residues that comprises this epitope. The information obtained will shine light on the mechanism of action of the disease. Such understanding could lead to therapeutic strategies for treating SOD1-mediated ALS. The BLI experiments carried out using the Octet QK system used C4F6 immobilized onto anti-mouse IgG Fc biosensors. The wild-type SOD1 and its variants showed changes in their affinity towards C4F6 as a result of the structure perturbations caused by mutagenesis and by chemical means. The data suggest that C4F6 recognizes and binds to an unusual conformation shared among misfolded variants of SOD1.

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