Licochalcone A selectively modulates mTORC1‐TFEB to enhance autophagy and demonstrates neuroprotective effects in a mouse model of Parkinson's disease
Abstract Activation of transcription factor EB (TFEB), a key regulator of autophagy induction and lysosomal biogenesis, is considered a promising therapeutic strategy for treating the currently incurable Parkinson's disease (PD). However, most TFEB activators also inhibit mTORC1, which regulate...
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| Format: | Article |
| Language: | English |
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Wiley
2025-06-01
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| Series: | Brain-X |
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| Online Access: | https://doi.org/10.1002/brx2.70031 |
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| author | Sisi Wang Ziyang Ding Zhou Zhu Xiaoru Zhong Ashok Iyaswamy Yaping Niu Wei Zhang Jichao Sun Yulin Feng Chuanbin Yang Jigang Wang |
| author_facet | Sisi Wang Ziyang Ding Zhou Zhu Xiaoru Zhong Ashok Iyaswamy Yaping Niu Wei Zhang Jichao Sun Yulin Feng Chuanbin Yang Jigang Wang |
| author_sort | Sisi Wang |
| collection | DOAJ |
| description | Abstract Activation of transcription factor EB (TFEB), a key regulator of autophagy induction and lysosomal biogenesis, is considered a promising therapeutic strategy for treating the currently incurable Parkinson's disease (PD). However, most TFEB activators also inhibit mTORC1, which regulates several other cellular pathways. Therefore, small molecules that selectively modulate the mTORC1‐TFEB pathway represent a novel and promising approach for treating PD. This study reveals that licochalcone A (LA), a flavonoid derived from the widely used Chinese herbal medicine licorice, selectively activates TFEB‐mediated autophagy and exerts neuroprotective effects in a mouse model of PD. Specifically, we found that LA promoted the displacement of TFEB to the nucleus and enhanced autophagic flux. Knockout of the TFEB gene effectively inhibited LA‐induced autophagy, suggesting that LA induced autophagy through TFEB activation. Mechanistic investigations revealed that LA activates TFEB through the Rag C‐mediated non‐canonical mTORC1 pathway, rather than through the canonical mTOR signaling or the PPP3/calcineurin pathway. Moreover, in a mouse model of MPTP‐induced PD, oral administration of LA reduced the depletion of dopaminergic cells in the striatum and substantia nigra and alleviated motor symptoms. In conclusion, LA selectively modulates the mTORC1‐TFEB pathway to induce autophagy, and reduces dopaminergic neuron loss and alleviates motor dysfunction in a mouse model of PD. These findings suggest that LA could serve as a novel TFEB activator and a potential therapeutic agent for treating PD. |
| format | Article |
| id | doaj-art-3a3c3b54aba343b1a52ca72dd7275e3f |
| institution | Kabale University |
| issn | 2835-3153 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Wiley |
| record_format | Article |
| series | Brain-X |
| spelling | doaj-art-3a3c3b54aba343b1a52ca72dd7275e3f2025-08-20T03:28:00ZengWileyBrain-X2835-31532025-06-0132n/an/a10.1002/brx2.70031Licochalcone A selectively modulates mTORC1‐TFEB to enhance autophagy and demonstrates neuroprotective effects in a mouse model of Parkinson's diseaseSisi Wang0Ziyang Ding1Zhou Zhu2Xiaoru Zhong3Ashok Iyaswamy4Yaping Niu5Wei Zhang6Jichao Sun7Yulin Feng8Chuanbin Yang9Jigang Wang10School of Pharmaceutical Sciences National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine Jiangxi University of Chinese Medicine Nanchang Jiangxi ChinaSchool of Pharmaceutical Sciences National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine Jiangxi University of Chinese Medicine Nanchang Jiangxi ChinaDepartment of Critical Care Medicine Guangdong Provincial Clinical Research Center for Geriatrics Shenzhen Clinical Research Center for Geriatrics Shenzhen People's Hospital (The Second Clinical Medical College Jinan University The First Affiliated Hospital Southern University of Science and Technology) Shenzhen Guangdong ChinaDepartment of Critical Care Medicine Guangdong Provincial Clinical Research Center for Geriatrics Shenzhen Clinical Research Center for Geriatrics Shenzhen People's Hospital (The Second Clinical Medical College Jinan University The First Affiliated Hospital Southern University of Science and Technology) Shenzhen Guangdong ChinaMr. & Mrs. Ko Chi‐Ming Centre for Parkinson's Disease Research School of Chinese Medicine Hong Kong Baptist University Hong Kong SAR ChinaSchool of Pharmaceutical Sciences National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine Jiangxi University of Chinese Medicine Nanchang Jiangxi ChinaGuangdong Provincial Key Laboratory for Research and Evaluation of Pharmaceutical Preparations Center for Drug Research and Development Guangdong Pharmaceutical University Guangzhou Guangdong ChinaDepartment of Critical Care Medicine Guangdong Provincial Clinical Research Center for Geriatrics Shenzhen Clinical Research Center for Geriatrics Shenzhen People's Hospital (The Second Clinical Medical College Jinan University The First Affiliated Hospital Southern University of Science and Technology) Shenzhen Guangdong ChinaSchool of Pharmaceutical Sciences National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine Jiangxi University of Chinese Medicine Nanchang Jiangxi ChinaDepartment of Critical Care Medicine Guangdong Provincial Clinical Research Center for Geriatrics Shenzhen Clinical Research Center for Geriatrics Shenzhen People's Hospital (The Second Clinical Medical College Jinan University The First Affiliated Hospital Southern University of Science and Technology) Shenzhen Guangdong ChinaSchool of Pharmaceutical Sciences National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine Jiangxi University of Chinese Medicine Nanchang Jiangxi ChinaAbstract Activation of transcription factor EB (TFEB), a key regulator of autophagy induction and lysosomal biogenesis, is considered a promising therapeutic strategy for treating the currently incurable Parkinson's disease (PD). However, most TFEB activators also inhibit mTORC1, which regulates several other cellular pathways. Therefore, small molecules that selectively modulate the mTORC1‐TFEB pathway represent a novel and promising approach for treating PD. This study reveals that licochalcone A (LA), a flavonoid derived from the widely used Chinese herbal medicine licorice, selectively activates TFEB‐mediated autophagy and exerts neuroprotective effects in a mouse model of PD. Specifically, we found that LA promoted the displacement of TFEB to the nucleus and enhanced autophagic flux. Knockout of the TFEB gene effectively inhibited LA‐induced autophagy, suggesting that LA induced autophagy through TFEB activation. Mechanistic investigations revealed that LA activates TFEB through the Rag C‐mediated non‐canonical mTORC1 pathway, rather than through the canonical mTOR signaling or the PPP3/calcineurin pathway. Moreover, in a mouse model of MPTP‐induced PD, oral administration of LA reduced the depletion of dopaminergic cells in the striatum and substantia nigra and alleviated motor symptoms. In conclusion, LA selectively modulates the mTORC1‐TFEB pathway to induce autophagy, and reduces dopaminergic neuron loss and alleviates motor dysfunction in a mouse model of PD. These findings suggest that LA could serve as a novel TFEB activator and a potential therapeutic agent for treating PD.https://doi.org/10.1002/brx2.700311‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)autophagylicochalcone AParkinson's diseaseRag GTPasetranscription factor EB (TFEB) |
| spellingShingle | Sisi Wang Ziyang Ding Zhou Zhu Xiaoru Zhong Ashok Iyaswamy Yaping Niu Wei Zhang Jichao Sun Yulin Feng Chuanbin Yang Jigang Wang Licochalcone A selectively modulates mTORC1‐TFEB to enhance autophagy and demonstrates neuroprotective effects in a mouse model of Parkinson's disease Brain-X 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) autophagy licochalcone A Parkinson's disease Rag GTPase transcription factor EB (TFEB) |
| title | Licochalcone A selectively modulates mTORC1‐TFEB to enhance autophagy and demonstrates neuroprotective effects in a mouse model of Parkinson's disease |
| title_full | Licochalcone A selectively modulates mTORC1‐TFEB to enhance autophagy and demonstrates neuroprotective effects in a mouse model of Parkinson's disease |
| title_fullStr | Licochalcone A selectively modulates mTORC1‐TFEB to enhance autophagy and demonstrates neuroprotective effects in a mouse model of Parkinson's disease |
| title_full_unstemmed | Licochalcone A selectively modulates mTORC1‐TFEB to enhance autophagy and demonstrates neuroprotective effects in a mouse model of Parkinson's disease |
| title_short | Licochalcone A selectively modulates mTORC1‐TFEB to enhance autophagy and demonstrates neuroprotective effects in a mouse model of Parkinson's disease |
| title_sort | licochalcone a selectively modulates mtorc1 tfeb to enhance autophagy and demonstrates neuroprotective effects in a mouse model of parkinson s disease |
| topic | 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) autophagy licochalcone A Parkinson's disease Rag GTPase transcription factor EB (TFEB) |
| url | https://doi.org/10.1002/brx2.70031 |
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