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...
| Published in: | Pharmacological Research |
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| Main Authors: | , , , , , , , , , , , , |
| Format: | Article |
| Language: | English |
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Elsevier
2024-12-01
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1043661824004638 |
| _version_ | 1849527993817366528 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Jing Wen |
| collection | DOAJ |
| container_title | Pharmacological Research |
| description | 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. |
| format | Article |
| id | doaj-art-e4ba3981426e4aba86d2d7d212d5061e |
| institution | Directory of Open Access Journals |
| issn | 1096-1186 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Elsevier |
| record_format | Article |
| spelling | doaj-art-e4ba3981426e4aba86d2d7d212d5061e2025-08-20T02:49:40ZengElsevierPharmacological Research1096-11862024-12-0121010751810.1016/j.phrs.2024.107518Lycorine protects motor neurons against TDP-43 proteinopathy-induced degeneration in cross-species models with amyotrophic lateral sclerosisJing Wen0Yunhao Li1Yanzhu Qin2Lingli Yan3Ke Zhang4Ang Li5Ziying Wang6Feng Yu7Jianheng Lai8Wei Yang9Yong U. Liu10Dajiang Qin11Huanxing Su12State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, MacaoState Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, MacaoKey Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510799, ChinaState Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, MacaoState Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, MacaoState Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, MacaoState Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, MacaoState Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, MacaoKey Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510799, ChinaThe Fourth Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; GuiZhou University Medical College, Guiyang 550025, ChinaLaboratory for Neuroimmunology in Health and Diseases, Center for Medical Research on Innovation and Translation, Institute of Clinical Medicine, the Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou 510180, China; Correspondence to: Bio-land CMRIT of Guangzhou First People’s Hospital, Room B-912, 10 Huanyu 2nd Road, Guangzhou, China.Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510799, China; Correspondence to: Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao; Correspondence to: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences (ICMS), University of Macau, Macao.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.http://www.sciencedirect.com/science/article/pii/S1043661824004638ALSTDP-43 proteinopathyLycorineUPSMotor neurons |
| spellingShingle | 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 Lycorine protects motor neurons against TDP-43 proteinopathy-induced degeneration in cross-species models with amyotrophic lateral sclerosis ALS TDP-43 proteinopathy Lycorine UPS Motor neurons |
| title | Lycorine protects motor neurons against TDP-43 proteinopathy-induced degeneration in cross-species models with amyotrophic lateral sclerosis |
| title_full | Lycorine protects motor neurons against TDP-43 proteinopathy-induced degeneration in cross-species models with amyotrophic lateral sclerosis |
| title_fullStr | Lycorine protects motor neurons against TDP-43 proteinopathy-induced degeneration in cross-species models with amyotrophic lateral sclerosis |
| title_full_unstemmed | Lycorine protects motor neurons against TDP-43 proteinopathy-induced degeneration in cross-species models with amyotrophic lateral sclerosis |
| title_short | Lycorine protects motor neurons against TDP-43 proteinopathy-induced degeneration in cross-species models with amyotrophic lateral sclerosis |
| title_sort | lycorine protects motor neurons against tdp 43 proteinopathy induced degeneration in cross species models with amyotrophic lateral sclerosis |
| topic | ALS TDP-43 proteinopathy Lycorine UPS Motor neurons |
| url | http://www.sciencedirect.com/science/article/pii/S1043661824004638 |
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