Amyotrophic lateral sclerosis(ALS)involves the fibrillization of copper,zinc superoxide dismutase(SOD1)and TAR DNAbinding protein 43 kDa(TDP-43).However,how SOD1-catalyzed reaction product hydrogen peroxide affects amyloid formation of SOD1 remains elusive.Here we study the effects of hydrogen peroxide on amyloid formation and cytotoxicity of wild-type human SOD1 and wild-type human TDP-43.We demonstrate that hydrogen peroxide at low concentrations triggers the fibrillization of wild-type SOD1 both in vitro and in SH-SY5Y neuroblastoma cells.Using an α-dimedone antibody that detects sulfenic acid modification of SOD1,we found that Cys-111 in wild-type SOD1 is oxidized to C-SOH by H2O2 at low concentrations both in vitro and in cells,followed by the formation of oxidized SOD1 oligomers and fibrils.Furthermore,we show that oxidized SOD1 oligomers not only drive wild-type SOD1 to form fibrils in the cytoplasm but also induce cytoplasm mislocalization and the subsequent fibrillization of wild-type TDP-43 in SH-SY5Y cells,thereby inducing early and late apoptosis of living SH-SY5Y cells.Thus,we propose that H2O2 at low concentrations triggers the fibrillization of wild-type SOD1 and subsequently induces SOD1 toxicity and TDP-43 toxicity in neuronal cells via sulfenic acid modification of Cys-111 in SOD1.Our findings provide clear evidence for the pathology of sporadic ALS that pathological hydrogen peroxide should be taken into account.