Dose imbalance of DYRK1A kinase causes systemic progeroid status in Down syndrome by increasing the un-repaired DNA damage and reducing LaminB1 levels
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Le résumé fourni par la source
BACKGROUND: People with Down syndrome (DS) show clinical signs of accelerated ageing. Causative mechanisms remain unknown and hypotheses range from the (essentially untreatable) amplified-chromosomal-instability explanation, to potential actions of individual supernumerary chromosome-21 genes. The latter explanation could open a route to therapeutic amelioration if the specific over-acting genes could be identified and their action toned-down. METHODS: Biological age was estimated through patterns of sugar molecules attached to plasma immunoglobulin-G (IgG-glycans, an established "biological-ageing-clock") in n = 246 individuals with DS from three European populations, clinically characterised for the presence of co-morbidities, and compared to n = 256 age-, sex- and demography-matched healthy controls. Isogenic human induced pluripotent stem cell (hiPSCs) models of full and partial trisomy-21 with CRISPR-Cas9 gene editing and two kinase inhibitors were studied prior and after differentiation to cerebral organoids. FINDINGS: Biological age in adults with DS is (on average) 18.4-19.1 years older than in chronological-age-matched controls independent of co-morbidities, and this shift remains constant throughout lifespan. Changes are detectable from early childhood, and do not require a supernumerary chromosome, but are seen in segmental duplication of only 31 genes, along with increased DNA damage and decreased levels of LaminB1 in nucleated blood cells. We demonstrate that these cell-autonomous phenotypes can be gene-dose-modelled and pharmacologically corrected in hiPSCs and derived cerebral organoids. Using isogenic hiPSC models we show that chromosome-21 gene DYRK1A overdose is sufficient and necessary to cause excess unrepaired DNA damage. INTERPRETATION: Explanation of hitherto observed accelerated ageing in DS as a developmental progeroid syndrome driven by DYRK1A overdose provides a target for early pharmacological preventative intervention strategies. FUNDING: Main funding came from the "Research Cooperability" Program of the Croatian Science Foundation funded by the European Union from the European Social Fund under the Operational Programme Efficient Human Resources 2014-2020, Project PZS-2019-02-4277, and the Wellcome Trust Grants 098330/Z/12/Z and 217199/Z/19/Z (UK). All other funding is described in details in the "Acknowledgements".
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Dose imbalance of DYRK1A kinase causes systemic progeroid status in Down syndrome by increasing the un-repaired DNA damage and reducing LaminB1 levels
- Date Crossref
- 01/08/2023
- Éditeur
- Elsevier BV
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Queen Mary University of London Birkbeck pays non établi dans la noticeUniversité ou école supérieure
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Blizard Institute pays non établi dans la noticeUniversité ou école supérieure
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Nanyang Technological University pays non établi dans la noticeUniversité ou école supérieure
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Genos (Croatia) pays non établi dans la noticeEntreprise
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Science Research Laboratory pays non établi dans la noticeStructure de recherche
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Agency for Science pays non établi dans la noticeOrganisme public
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University of Bologna Department of Medical and Surgical Sciences pays non établi dans la noticeUniversité ou école supérieure
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University of Zagreb pays non établi dans la noticeUniversité ou école supérieure
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Institute of Molecular and Cell Biology pays non établi dans la noticeStructure de recherche
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Genome Institute of Singapore pays non établi dans la noticeStructure de recherche
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King's College London Department of Forensic and Neurodevelopmental Sciences pays non établi dans la noticeUniversité ou école supérieure
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University College London Division of Psychiatry pays non établi dans la noticeUniversité ou école supérieure
Birkbeck — Queen Mary University of London, Blizard Institute et Nanyang Technological University, avec 9 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.