{"title":"Artemisinin alleviates Parkinson’s disease by targeting Adcy5-Gch1 axis to trigger a cascade generation of BH4 and dopamine in rats","authors":"Xin-xing Yang, Guo-qing Wang, Qian Wen, Yu-jia Zhao, Dai-di Li, Feng Zhang","doi":"10.1186/s13059-025-03712-5","DOIUrl":null,"url":null,"abstract":"Parkinson’s disease is a highly prevalent neurodegenerative disorder. Hyposecretion of dopamine (DA) is the end result in the pathology of Parkinson’s disease. Unfortunately, safe and efficient therapeutic drugs are deficient. Tyrosine hydroxylase is the rate-limiting enzyme for DA synthesis, could hydroxylate tyrosine and generate levodopa with tetrahydrobiopterin (BH4) as an indispensable coenzyme. Furthermore, BH4 was confirmed to confer neuroprotection against Parkinson’s disease. Thus, regulation of BH4 synthesis was verified to become a promising therapeutic strategy for Parkinson’s disease. We demonstrate that artemisinin effectively produced neuroprotection against Parkinson’s disease in rats. Integrated analysis of midbrain proteomics and non-targeted metabolomics suggests that artemisinin might target adenylate cyclase 5 (Adcy5) to increase GTP cyclohydrolase 1 (Gch1, BH4 synthetase) expression to further boost BH4 synthesis. To verify this hypothesis, molecular docking experiments demonstrate that ART could directly bind to Adcy5. Artemisinin increases Adcy5 and Gch1 expressions and BH4 production both in vivo and in vitro. Further rescue experiments demonstrate that artemisinin-generated DA neuroprotection and hypersecretion of DA and BH4 disappears after inhibition of Adcy5 or Gch1 in vitro. Additionally, suppression of Adcy5 aggravates Parkinson’s disease manifestation, decreases midbrain DA and BH4 production and down-regulated Gch1 expression in vivo. Artemisinin mediates neuroprotection against Parkinson’s disease via regulation of Adcy5-Gch1-BH4 axis in rats. These findings present a beneficial potential for future application of artemisinin on Parkinson’s disease treatment. ","PeriodicalId":12611,"journal":{"name":"Genome Biology","volume":"21 1","pages":""},"PeriodicalIF":10.1000,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Genome Biology","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1186/s13059-025-03712-5","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOTECHNOLOGY & APPLIED MICROBIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Parkinson’s disease is a highly prevalent neurodegenerative disorder. Hyposecretion of dopamine (DA) is the end result in the pathology of Parkinson’s disease. Unfortunately, safe and efficient therapeutic drugs are deficient. Tyrosine hydroxylase is the rate-limiting enzyme for DA synthesis, could hydroxylate tyrosine and generate levodopa with tetrahydrobiopterin (BH4) as an indispensable coenzyme. Furthermore, BH4 was confirmed to confer neuroprotection against Parkinson’s disease. Thus, regulation of BH4 synthesis was verified to become a promising therapeutic strategy for Parkinson’s disease. We demonstrate that artemisinin effectively produced neuroprotection against Parkinson’s disease in rats. Integrated analysis of midbrain proteomics and non-targeted metabolomics suggests that artemisinin might target adenylate cyclase 5 (Adcy5) to increase GTP cyclohydrolase 1 (Gch1, BH4 synthetase) expression to further boost BH4 synthesis. To verify this hypothesis, molecular docking experiments demonstrate that ART could directly bind to Adcy5. Artemisinin increases Adcy5 and Gch1 expressions and BH4 production both in vivo and in vitro. Further rescue experiments demonstrate that artemisinin-generated DA neuroprotection and hypersecretion of DA and BH4 disappears after inhibition of Adcy5 or Gch1 in vitro. Additionally, suppression of Adcy5 aggravates Parkinson’s disease manifestation, decreases midbrain DA and BH4 production and down-regulated Gch1 expression in vivo. Artemisinin mediates neuroprotection against Parkinson’s disease via regulation of Adcy5-Gch1-BH4 axis in rats. These findings present a beneficial potential for future application of artemisinin on Parkinson’s disease treatment.
Genome BiologyBiochemistry, Genetics and Molecular Biology-Genetics
CiteScore
21.00
自引率
3.30%
发文量
241
审稿时长
2 months
期刊介绍:
Genome Biology stands as a premier platform for exceptional research across all domains of biology and biomedicine, explored through a genomic and post-genomic lens.
With an impressive impact factor of 12.3 (2022),* the journal secures its position as the 3rd-ranked research journal in the Genetics and Heredity category and the 2nd-ranked research journal in the Biotechnology and Applied Microbiology category by Thomson Reuters. Notably, Genome Biology holds the distinction of being the highest-ranked open-access journal in this category.
Our dedicated team of highly trained in-house Editors collaborates closely with our esteemed Editorial Board of international experts, ensuring the journal remains on the forefront of scientific advances and community standards. Regular engagement with researchers at conferences and institute visits underscores our commitment to staying abreast of the latest developments in the field.