Lycorine protects motor neurons against TDP-43 proteinopathy-induced degeneration in cross-species models with amyotrophic lateral sclerosis
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 nat...
Saved in:
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Book |
| Published: |
Elsevier,
2024-12-01T00:00:00Z.
|
| Subjects: | |
| Online Access: | Connect to this object online. |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| Summary: | 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. |
|---|---|
| Item Description: | 1096-1186 10.1016/j.phrs.2024.107518 |