Lycorine Protects Motor Neurons Against TDP-43 Proteinopathy in Animal Models with Amyotrophic Lateral Sclerosis

Aggregation of the TAR-DNA binding protein (TDP)-43 is a common pathological feature present in nearly 97% cases of amyotrophic lateral sclerosis (ALS) patients, making it an attractive target for pathogenic studies and drug screening. Here, by targeting the TDP-43A315T mutant, we performed a high-throughput screening of 1500 compounds from a natural product library and identified that lycorine, a naturally occurring alkaloid, significantly downregulated the expression of TDP-43A315T in a cellular model. We further demonstrate that lycorine inhibits the synthesis of TDP-43A315T and promotes the clearance of the mutant protein through the ubiquitin–proteasome system (UPS). Importantly, treatment of lycorine significantly attenuates TDP-43 proteinopathy and improves functional recovery in transgenic C. elegans and mice expressing TDP-43A315T. These findings suggest that lycorine is a promising lead compound that has therapeutic potential for ALS