Abstract
The molecular mechanisms underlying amyotrophic lateral sclerosis (ALS) are not fully understood, but oxidative stress is known to play a central role in ALS pathogenesis. In this study, we developed a method to induce gradual oxidative stress in iPSC-motor neurons, creating a model for studying neuronal damage in ALS. Neuroprotective effects in this model were observed with ferroptosis inhibitors as well as edaravone, an approved ALS medicine. Furthermore, through a compound screen, a cholesterol biosynthesis inhibitor, AY 9944, was identified as being capable of inhibiting neuronal damage in the model. Additionally, neuroprotective activity was observed with 7-dehydrocholesterol, an immediate precursor of cholesterol, while the efficacy of AY-9944 was compromised by knockout of the EBP gene, which encodes an enzyme involved in cholesterol biosynthesis. These findings suggest the involvement of ferroptosis and cholesterol biogenesis in progression of ALS and provide potential insights for drug development.