SecinH3 Attenuates TDP-43 p.Q331K-Induced Neuronal Toxicity by Suppressing Endoplasmic Reticulum Stress and Enhancing Autophagic Flux.

Amyotrophic lateral sclerosis (ALS) is a fatal, adult-onset, neurodegenerative disease. The transactivating response region DNA binding protein 43 (TDP-43) p.Q331K mutation (TDP-43 Q331K) has previously been identified in ALS as a disease-causing mutation with neurotoxicity. SecinH3, a cytohesin inhibitor, has neuroprotective effects against mutant superoxide dismutase 1 (SOD1) toxicity. However, whether SecinH3 protects against mutant TDP-43 p.Q331K protein toxicity and its potential molecular mechanisms have not yet been investigated. To determine whether TDP-43 Q331K induces neuronal toxicity, SH-SY5Y, a human derived neuronal cell line were selected as an in vitro model of neuronal function. SH-SY5Y cells were transiently transfected with TDP-43 wild-type or TDP-43 Q331K. Remarkably, TDP-43 Q331K induced neuronal damage via endoplasmic reticulum (ER) stress-mediated apoptosis and the impairment of the autophagic flux. SecinH3 was demonstrated to successfully attenuate the TDP-43 Q331K-induced neuronal toxicity by suppressing ER stress-mediated apoptosis and enhancing the autophagic flux. Taken together, our in vitro study provided evidence that SecinH3 exerts neuroprotective effects against TDP-43 Q331K-mediated neuronal toxicity and was able to elucidate its mode of action. SecinH3 could, therefore, be considered a promising candidate as a therapeutic agent of ALS.