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
Products used in the paper Details Operation
AAV vector packaging Single-strand, adenovirus-associated viral vectors CaMKIIa::mScarlet and CaMKIIa::mTDP43 (A315T, mutNLS)-mScarlet were constructed by PackGene® Biotech, LLC. Request Quote

Research Field: CNS

Keywords: Amyotrophic lateral sclerosis, TDP-43, Lycorine, Ubiquitin-proteasome system (UPS), Motor neurons

AAV Serotype: AAV9

Dose: Viral titers (300 nL) at a concentration of 5 x 10^12 GC/mL were stereotaxic injected into the primary motor cortex of the mice under anesthesia with 1.5% isoflurane.

Routes of Administration: stereotaxic injected into the primary motor cortex of the mice

Targeted organ: brain

Animal or cell line strain: In all experiments, 8–10-week-old male and female C57BL/6J mice were used.


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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