Dose imbalance of DYRK1A kinase causes systemic progeroid status in Down syndrome by increasing the un-repaired DNA damage and reducing LaminB1 levelsResearch in context
Summary: 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 ge...
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Elsevier
2023-08-01
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| Series: | EBioMedicine |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396423002578 |
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| author | Aoife Murray Gillian Gough Ana Cindrić Frano Vučković David Koschut Vincenzo Borelli Dražen J. Petrović Ana Bekavac Ante Plećaš Valentina Hribljan Reinhard Brunmeir Julija Jurić Maja Pučić-Baković Anita Slana Helena Deriš Azra Frkatović Jűrgen Groet Niamh L. O’Brien Hong Yu Chen Yee Jie Yeap Frederic Delom Steven Havlicek Luke Gammon Sarah Hamburg Carla Startin Hana D’Souza Dinko Mitrečić Mijana Kero Ljubica Odak Božo Krušlin Željka Krsnik Ivica Kostović Jia Nee Foo Yuin-Han Loh Norris Ray Dunn Susana de la Luna Tim Spector Ingeborg Barišić Michael S.C. Thomas Andre Strydom Claudio Franceschi Gordan Lauc Jasminka Krištić Ivan Alić Dean Nižetić |
| author_facet | Aoife Murray Gillian Gough Ana Cindrić Frano Vučković David Koschut Vincenzo Borelli Dražen J. Petrović Ana Bekavac Ante Plećaš Valentina Hribljan Reinhard Brunmeir Julija Jurić Maja Pučić-Baković Anita Slana Helena Deriš Azra Frkatović Jűrgen Groet Niamh L. O’Brien Hong Yu Chen Yee Jie Yeap Frederic Delom Steven Havlicek Luke Gammon Sarah Hamburg Carla Startin Hana D’Souza Dinko Mitrečić Mijana Kero Ljubica Odak Božo Krušlin Željka Krsnik Ivica Kostović Jia Nee Foo Yuin-Han Loh Norris Ray Dunn Susana de la Luna Tim Spector Ingeborg Barišić Michael S.C. Thomas Andre Strydom Claudio Franceschi Gordan Lauc Jasminka Krištić Ivan Alić Dean Nižetić |
| author_sort | Aoife Murray |
| collection | DOAJ |
| description | Summary: 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”. |
| first_indexed | 2024-03-12T15:31:04Z |
| format | Article |
| id | doaj.art-fccbd6f8ccf04865a74224623e30be79 |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-03-12T15:31:04Z |
| publishDate | 2023-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-fccbd6f8ccf04865a74224623e30be792023-08-10T04:34:28ZengElsevierEBioMedicine2352-39642023-08-0194104692Dose imbalance of DYRK1A kinase causes systemic progeroid status in Down syndrome by increasing the un-repaired DNA damage and reducing LaminB1 levelsResearch in contextAoife Murray0Gillian Gough1Ana Cindrić2Frano Vučković3David Koschut4Vincenzo Borelli5Dražen J. Petrović6Ana Bekavac7Ante Plećaš8Valentina Hribljan9Reinhard Brunmeir10Julija Jurić11Maja Pučić-Baković12Anita Slana13Helena Deriš14Azra Frkatović15Jűrgen Groet16Niamh L. O’Brien17Hong Yu Chen18Yee Jie Yeap19Frederic Delom20Steven Havlicek21Luke Gammon22Sarah Hamburg23Carla Startin24Hana D’Souza25Dinko Mitrečić26Mijana Kero27Ljubica Odak28Božo Krušlin29Željka Krsnik30Ivica Kostović31Jia Nee Foo32Yuin-Han Loh33Norris Ray Dunn34Susana de la Luna35Tim Spector36Ingeborg Barišić37Michael S.C. Thomas38Andre Strydom39Claudio Franceschi40Gordan Lauc41Jasminka Krištić42Ivan Alić43Dean Nižetić44Faculty of Medicine and Dentistry, Blizard Institute, Queen Mary University of London, London, UK; The London Down Syndrome Consortium (LonDownS), London, UK; Corresponding author. Faculty of Medicine and Dentistry, Blizard Institute, Queen Mary University of London, London, UK.Lee Kong Chian School of Medicine, Nanyang Technological University, SingaporeGlycoscience Research Laboratory, Genos Ltd., Zagreb, CroatiaGlycoscience Research Laboratory, Genos Ltd., Zagreb, CroatiaLee Kong Chian School of Medicine, Nanyang Technological University, Singapore; Disease Intervention Technology Laboratory (DITL), Institute of Molecular and Cellular Biology (IMCB), Agency for Science, Technology and Research (A∗STAR), SingaporeDepartment of Medical and Surgical Sciences, Alma Mater Studiorum University of Bologna, ItalyGlycoscience Research Laboratory, Genos Ltd., Zagreb, Croatia; Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Zagreb, CroatiaCroatian Institute for Brain Research, School of Medicine, University of Zagreb, Zagreb, CroatiaFaculty of Veterinary Medicine, Department of Anatomy, Histology and Embryology, University of Zagreb, Zagreb, CroatiaCroatian Institute for Brain Research, School of Medicine, University of Zagreb, Zagreb, CroatiaLee Kong Chian School of Medicine, Nanyang Technological University, SingaporeGlycoscience Research Laboratory, Genos Ltd., Zagreb, CroatiaGlycoscience Research Laboratory, Genos Ltd., Zagreb, CroatiaGlycoscience Research Laboratory, Genos Ltd., Zagreb, CroatiaGlycoscience Research Laboratory, Genos Ltd., Zagreb, CroatiaGlycoscience Research Laboratory, Genos Ltd., Zagreb, CroatiaFaculty of Medicine and Dentistry, Blizard Institute, Queen Mary University of London, London, UK; The London Down Syndrome Consortium (LonDownS), London, UKFaculty of Medicine and Dentistry, Blizard Institute, Queen Mary University of London, London, UK; The London Down Syndrome Consortium (LonDownS), London, UKInstitute of Molecular and Cell Biology (IMCB), A∗STAR, SingaporeLee Kong Chian School of Medicine, Nanyang Technological University, SingaporeFaculty of Medicine and Dentistry, Blizard Institute, Queen Mary University of London, London, UKLaboratory of Neurogenetics, Genome Institute of Singapore, A∗STAR, SingaporeFaculty of Medicine and Dentistry, Blizard Institute, Queen Mary University of London, London, UKThe London Down Syndrome Consortium (LonDownS), London, UKThe London Down Syndrome Consortium (LonDownS), London, UK; Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK; Division of Psychiatry, University College London, London, UK; School of Psychology, University of Roehampton, London, UKThe London Down Syndrome Consortium (LonDownS), London, UK; Centre for Brain and Cognitive Development, Birkbeck, University of London, London, UKCroatian Institute for Brain Research, School of Medicine, University of Zagreb, Zagreb, CroatiaDepartment of Medical Genetics, Children’s Hospital Zagreb, Centre of Excellence for Reproductive and Regenerative Medicine, School of Medicine, University of Zagreb, Zagreb, CroatiaDepartment of Medical Genetics, Children’s Hospital Zagreb, Centre of Excellence for Reproductive and Regenerative Medicine, School of Medicine, University of Zagreb, Zagreb, CroatiaDepartment of Pathology, School of Medicine, University of Zagreb, Zagreb, CroatiaCroatian Institute for Brain Research, School of Medicine, University of Zagreb, Zagreb, CroatiaCroatian Institute for Brain Research, School of Medicine, University of Zagreb, Zagreb, CroatiaLee Kong Chian School of Medicine, Nanyang Technological University, Singapore; Laboratory of Neurogenetics, Genome Institute of Singapore, A∗STAR, SingaporeInstitute of Molecular and Cell Biology (IMCB), A∗STAR, SingaporeLee Kong Chian School of Medicine, Nanyang Technological University, Singapore; Institute of Molecular and Cell Biology (IMCB), A∗STAR, SingaporeICREA, Genome Biology Programme (CRG), Universitat Pompeu Fabra (UPF), CIBER of Rare Diseases, Barcelona, SpainDepartment of Twin Research and Genetic Epidemiology, King's College London, London, UKDepartment of Medical Genetics, Children’s Hospital Zagreb, Centre of Excellence for Reproductive and Regenerative Medicine, School of Medicine, University of Zagreb, Zagreb, CroatiaThe London Down Syndrome Consortium (LonDownS), London, UK; Centre for Brain and Cognitive Development, Birkbeck, University of London, London, UKThe London Down Syndrome Consortium (LonDownS), London, UK; Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK; Division of Psychiatry, University College London, London, UKDepartment of Medical and Surgical Sciences, Alma Mater Studiorum University of Bologna, Italy; Institute of Information Technologies, Mathematics and Mechanics, Lobachevsky State University, Nizhny Novgorod 603022, RussiaGlycoscience Research Laboratory, Genos Ltd., Zagreb, Croatia; Faculty of Pharmacy and Biochemistry, University of Zagreb, Zagreb, CroatiaGlycoscience Research Laboratory, Genos Ltd., Zagreb, Croatia; Corresponding author: Glycoscience Research Laboratory, Genos Ltd., Zagreb, Croatia.Faculty of Medicine and Dentistry, Blizard Institute, Queen Mary University of London, London, UK; Faculty of Veterinary Medicine, Department of Anatomy, Histology and Embryology, University of Zagreb, Zagreb, Croatia; Corresponding author. Faculty of Medicine and Dentistry, Blizard Institute, Queen Mary University of London, London, UK.Faculty of Medicine and Dentistry, Blizard Institute, Queen Mary University of London, London, UK; The London Down Syndrome Consortium (LonDownS), London, UK; Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore; Corresponding author. Faculty of Medicine and Dentistry, Blizard Institute, Queen Mary University of London, London, UK.Summary: 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”.http://www.sciencedirect.com/science/article/pii/S2352396423002578Down syndromeDown syndrome critical regionChromosome 21AgeingDYRK1ADYRK1A inhibitors |
| spellingShingle | Aoife Murray Gillian Gough Ana Cindrić Frano Vučković David Koschut Vincenzo Borelli Dražen J. Petrović Ana Bekavac Ante Plećaš Valentina Hribljan Reinhard Brunmeir Julija Jurić Maja Pučić-Baković Anita Slana Helena Deriš Azra Frkatović Jűrgen Groet Niamh L. O’Brien Hong Yu Chen Yee Jie Yeap Frederic Delom Steven Havlicek Luke Gammon Sarah Hamburg Carla Startin Hana D’Souza Dinko Mitrečić Mijana Kero Ljubica Odak Božo Krušlin Željka Krsnik Ivica Kostović Jia Nee Foo Yuin-Han Loh Norris Ray Dunn Susana de la Luna Tim Spector Ingeborg Barišić Michael S.C. Thomas Andre Strydom Claudio Franceschi Gordan Lauc Jasminka Krištić Ivan Alić Dean Nižetić Dose imbalance of DYRK1A kinase causes systemic progeroid status in Down syndrome by increasing the un-repaired DNA damage and reducing LaminB1 levelsResearch in context EBioMedicine Down syndrome Down syndrome critical region Chromosome 21 Ageing DYRK1A DYRK1A inhibitors |
| title | Dose imbalance of DYRK1A kinase causes systemic progeroid status in Down syndrome by increasing the un-repaired DNA damage and reducing LaminB1 levelsResearch in context |
| title_full | Dose imbalance of DYRK1A kinase causes systemic progeroid status in Down syndrome by increasing the un-repaired DNA damage and reducing LaminB1 levelsResearch in context |
| title_fullStr | Dose imbalance of DYRK1A kinase causes systemic progeroid status in Down syndrome by increasing the un-repaired DNA damage and reducing LaminB1 levelsResearch in context |
| title_full_unstemmed | Dose imbalance of DYRK1A kinase causes systemic progeroid status in Down syndrome by increasing the un-repaired DNA damage and reducing LaminB1 levelsResearch in context |
| title_short | Dose imbalance of DYRK1A kinase causes systemic progeroid status in Down syndrome by increasing the un-repaired DNA damage and reducing LaminB1 levelsResearch in context |
| title_sort | dose imbalance of dyrk1a kinase causes systemic progeroid status in down syndrome by increasing the un repaired dna damage and reducing laminb1 levelsresearch in context |
| topic | Down syndrome Down syndrome critical region Chromosome 21 Ageing DYRK1A DYRK1A inhibitors |
| url | http://www.sciencedirect.com/science/article/pii/S2352396423002578 |
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