Parsing disease‐relevant protein modifications from epiphenomena: perspective on the structural basis of SOD1‐mediated ALS

Most human proteins are post‐translationally modified from simple N‐terminal acetylation to complex phosphorylation, lipidation and glycosylation patterns. These processes, among others, result in multiple natural proteoforms of each protein. Conversely, aberrant protein modifications can result from changes in post‐translational processing and protein catabolism, xenobiotics and genetic mutation. Changes in protein amino acid composition can lead to changes in their secondary, tertiary and quaternary structures, including aggregation. In the first part of this perspective article, Jeffery Agar and co‐worker demonstrate that diverse Cu/Zn‐superoxide dismutase protein mutations result in a common structural consequence that can lead to toxic protein aggregation. In the second part of this perspective, they present evidence of both toxic and protective post‐translational modifications in human tissue, and how these informed our current therapeutic strategies. Dr. Jeffrey Agar is Associate Professor of Chemistry at Northeastern University (Boston, MA). His research interests are centered on the characterization of proteins post‐translational modifications and changes in protein, peptide, and lipid expression that occur during in disease, more specifically amyotrophic lateral sclerosis.