Fig. 8: A hypothetical model shows how pathologic concentration of hydrogen peroxide triggers the misfolding of SOD1 via sulfenic acid modification of Cys-111, and thus induces SOD1 toxicity and TDP-43 toxicity in neuronal cells

Nascent SOD1 (purple unfolded monomer, apo-SOD1) overexpressed in SH-SY5Y cells emerges from the ribosome (light green), copper (blue triangle), and zinc (orange square) bind to the correct binding sites, and the disulfide bond and mature SOD1 (purple dimer) are formed step by step (a). Mature SOD1 catalyzes the dismutation of superoxide anion (\({\mathrm{O}}_{\mathrm{2}}^{ \bullet - }\)) to H₂O₂ and O₂, and pathological concentration of the product H₂O₂ (red) abnormally accumulated in cytoplasm of SH-SY5Y cells could then trigger the oligomerization and fibrillization of nascent SOD1 via sulfenic acid modification of Cys-111 (from SOD1-SH to SOD1-SOH, purple), forming sulfenic acid-modified SOD1 oligomers (purple balls) and amyloid fibrils (purple bars) in SH-SY5Y cells (a). Sulfenic acid-modified SOD1 oligomers could induce cytoplasm mislocalization of human TDP-43 (green) (from the nucleus to the cytosol), forming cytoplasmic TDP-43 oligomers (green balls) and cytoplasmic fibrils (green bars), and induce apoptosis of living SH-SY5Y cells, thereby increasing the cytotoxicity of SOD1 and TDP-43 (a). Phosphatidylserine (a) is indicated by blue sticks with green balls. Scheme describing the competition between the major pathway, in which pathological concentration of H₂O₂ oxidizes human SOD1 to SOD1-SOH and drives human SOD1 to form highly toxic oligomers and fibrils, and another pathway, in which H₂O₂ at high concentrations over-oxidizes human SOD1 to SOD1-SO₂H and SOD1-SO₃H and drives human SOD1 to form non-amyloid aggregates (b)