Lycorine Protects Motor Neurons Against TDP-43 Proteinopathy in Animal Models with Amyotrophic Lateral Sclerosis
Brief intro:
- Author: Jing Wen, Yunhao Li, Zongqin Xiang, Bin Mou, Ke Zhang, Ang Li, Lingli Yan, Wei Yang, Yong U. Liu, Huanxing Su
- Journal: Neurology eJournal
- Doi: https://www.doi.org/10.2139/ssrn.4390302
- Publication Date: 2023 Mar 29
Products/Services used in the paper
Quotation shows PackGene:Single-strand, adenovirus-associated viral vectors CaMKIIa::mScarlet and CaMKIIa::mTDP43 (A315T, mutNLS)-mScarlet were constructed by PackGene Biotech.
Research Field:CNS
AAV Serotype:AAV9
Targeted organ:brain
Animal or cell line strain:In all experiments, 8–10-week-old male and female C57BL/6J mice were used.
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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