Fig. 7: Proposed mechanism of sALS development from wild-type SOD1.
a Newly synthesized SOD1 does not have Cu2+, and the cysteine residues are reduced, resulting in apo-SOD1 in an equilibrium between the monomeric and dimeric forms. b In the normoxic state, apo-SOD1 undergoes the maturation process. Disulfide bond formation and copper insertion occur by hCCS, resulting in holo-SOD1 with full superoxide dismutase activity. Under hypoxic conditions, disulfide bond formation by hCCS is inhibited, and immature apo-SOD1 accumulates in the cytosol. c In the presence of excess ROS, such as HOCl, with unknown environmental factors, a small amount of apo-SOD1 is overoxidized in an irreversible manner, resulting in ox-SOD1. d The structure of Ox-SOD1 with the open conformation in loop IV starts to form a short filamentous structure. e Filamentous ox-SOD1 is rapidly elongated by recruiting apo-SOD1, resulting in the ox-apo-SOD1 filament. f Filamentous ox-apo-SOD1 propagates to other regions in neurons or adjacent neuronal cells.
