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Pharmacological research

Pharmacological research

IF: 9.1
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Lycorine protects motor neurons against TDP-43 proteinopathy-induced degeneration in cross-species models with amyotrophic lateral sclerosis

Published:1 December 2024 DOI: PMID: 39603574
Jing Wen , Yunhao Li , Yanzhu Qin , Lingli Yan , Ke Zhang , Ang Li , Ziying Wang , Feng Yu , Jianheng Lai , Wei Yang , Yong U. Liu , Dajiang Qin , Huanxing Su

Abstract

Aggregation of TAR-DNA binding protein-43 (TDP-43) is a pathological feature present in nearly 97?% cases of amyotrophic lateral sclerosis (ALS), making it an attractive target for pathogenic studies and drug screening. Here, we have performed a high-throughput screening of 1500 compounds from a natural product library and identified that lycorine, a naturally occurring alkaloid, significantly decreases the level of TDP-43A315T in a cellular model. We further demonstrate that lycorine reduces the level of TDP-43A315T both through inhibiting its synthesis and by promoting its degradation by the ubiquitin-proteasome system (UPS). Importantly, treatment with lycorine significantly attenuates TDP-43 proteinopathy and improves functional recovery in TDP-43A315T-expressing Caenorhabditis elegans and mouse models. These findings suggest that lycorine is a promising lead compound that has therapeutic potential for ALS.

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