Neurology eJournal. 2023 Mar 29
Jing Wen, Yunhao Li, Zongqin Xiang, Bin Mou, Ke Zhang, Ang Li, Lingli Yan, Wei Yang, Yong U. Liu, Huanxing Su
Jing Wen, Yunhao Li, Zongqin Xiang, Bin Mou, Ke Zhang, Ang Li, Lingli Yan, Wei Yang, Yong U. Liu, Huanxing Su
Abstract
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
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