Abstract
A prion-like mechanism has been developed to explain the observed promotion of amyloid aggregation caused by conversion of structurally intact SOD1 to a misfolded form. Superoxide dismutase [Cu-Zn], or SOD1, is a homo-dimeric protein that functions as an antioxidant by scavenging for superoxide. The misfolding and aggregation of SOD1 is linked to inherited, or familial, amyotrophic lateral sclerosis (FALS), a progressive and fatal neurodegenerative disease. Aberrant SOD1 folding has also been strongly implicated in disease causation for sporadic ALS, or SALS, which accounts for ~90% of ALS cases. Studies have found that mutant, misfolded SOD1 can convert wtSOD1 in a prion-like fashion, and that misfolded wtSOD1 can be propagated by release and uptake of protein aggregates. Here it is demonstrated that enervating the SOD1 electrostatic loop can lead to an experimentally observed gain of interaction (GOI) responsible for the formation of SOD1 amyloid-like filaments. This enervation is caused in turn by the formation of transient, non-obligate oligomers between pathogenic SOD1 mutants and wt SOD1.