TY - JOUR
T1 - Dose imbalance of DYRK1A kinase causes systemic progeroid status in Down syndrome by increasing the un-repaired DNA damage and reducing LaminB1 levels
AU - Strydom, Andre
N1 - Funding Information:
This work has been supported by 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 (to GL and DN). This work has been also supported in part by the European Structural and Investment funding for the ‘ Croatian National Centre of Research Excellence in Personalized Healthcare ’, contract #KK.01.1.1.01.0010 (to GL); ‘ Centre of Competences in Molecular Diagnostics ’, contract #KK.01.2.2.03.0006 (to GL); the European Regional Development Fund grant ‘ CardioMetabolic ’ agreement #KK.01.2.1.02.0321 (to GL). DN was also funded by the Singapore Ministry of Education Academic Research Fund Tier 2 grants ( 2015-T2-1-023 & 2015-T2-2-119 ) and the Wellcome Trust Collaborative Award in Science 217199/Z/19/Z . The teams of AStr, MT and DN also received funding from the Wellcome Trust “LonDownS Consortium” Strategic Funding Award ( 098330/Z/12/Z ) (UK). In addition, AStr was supported by funding from the MRC ( Medical Research Council grants MRC S011277/1 , MR/S005145/1 (from Centers of Excellence in Neurodegeneration research) and MR/R024901/1 (from JPND). This work was also supported by Waterloo Foundation and Baily Thomas Charitable Fund (to MT). AM was awarded a William Harvey Academy Fellowship, co-funded by the People Programme (Marie Curie Actions) under REA no. 608765 . IA was awarded an Adris Foundation grant (251-61-01/139-22-01). The work of doctoral student HD has been supported by the “Young researchers' career development project—training of doctoral students” of the Croatian Science Foundation . DM was supported by the Croatian Science Foundation project Orastem ( IP-16-6-9451 ) and the European Union through the European Regional Development Fund , as the Scientific Centre of Excellence for Basic, Clinical and Translational Neuroscience under Grant Agreement No. KK.01.1.1.01.0007 . JNF received funding from the National Medical Research Council , Singapore ( MOH-000559 ). SdlL received funding from a Spanish Ministry of Science and Innovation grant PID2019-107185GB-I00 . We thank the CRB-BioJeL biobank for access to plasma samples of the adult cohort from France. We thank the LonDownS Consortium, the MRC (UK) foetal tissue bank, the Galliera Genetic Bank and the Italian Telethon biobank for providing samples. The authors thank Željka Punčec, Ana Bosak, and Danica Budinščak for technical help and Cleo Bishop for critical reading of the manuscript. We thank staff at the BALM, FACS, Genome Centre core facilities at the Blizard Institute.
Funding Information:
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”.This work has been supported by 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 (to GL and DN). This work has been also supported in part by the European Structural and Investment funding for the ‘Croatian National Centre of Research Excellence in Personalized Healthcare’, contract #KK.01.1.1.01.0010 (to GL); ‘Centre of Competences in Molecular Diagnostics’, contract #KK.01.2.2.03.0006 (to GL); the European Regional Development Fund grant ‘CardioMetabolic’ agreement #KK.01.2.1.02.0321 (to GL). DN was also funded by the Singapore Ministry of Education Academic Research Fund Tier 2 grants (2015-T2-1-023 & 2015-T2-2-119) and the Wellcome Trust Collaborative Award in Science 217199/Z/19/Z. The teams of AStr, MT and DN also received funding from the Wellcome Trust “LonDownS Consortium” Strategic Funding Award (098330/Z/12/Z) (UK). In addition, AStr was supported by funding from the MRC (Medical Research Council grants MRC S011277/1, MR/S005145/1 (from Centers of Excellence in Neurodegeneration research) and MR/R024901/1 (from JPND). This work was also supported by Waterloo Foundation and Baily Thomas Charitable Fund (to MT). AM was awarded a William Harvey Academy Fellowship, co-funded by the People Programme (Marie Curie Actions) under REA no. 608765. IA was awarded an Adris Foundation grant (251-61-01/139-22-01). The work of doctoral student HD has been supported by the “Young researchers' career development project—training of doctoral students” of the Croatian Science Foundation. DM was supported by the Croatian Science Foundation project Orastem (IP-16-6-9451) and the European Union through the European Regional Development Fund, as the Scientific Centre of Excellence for Basic, Clinical and Translational Neuroscience under Grant Agreement No. KK.01.1.1.01.0007. JNF received funding from the National Medical Research Council, Singapore (MOH-000559). SdlL received funding from a Spanish Ministry of Science and Innovation grant PID2019-107185GB-I00. We thank the CRB-BioJeL biobank for access to plasma samples of the adult cohort from France. We thank the LonDownS Consortium, the MRC (UK) foetal tissue bank, the Galliera Genetic Bank and the Italian Telethon biobank for providing samples. The authors thank Željka Punčec, Ana Bosak, and Danica Budinščak for technical help and Cleo Bishop for critical reading of the manuscript. We thank staff at the BALM, FACS, Genome Centre core facilities at the Blizard Institute.
Publisher Copyright:
© 2023 The Author(s)
PY - 2023/8
Y1 - 2023/8
N2 - BackgroundPeople 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.MethodsBiological 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.FindingsBiological 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.InterpretationExplanation 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.FundingMain 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”.
AB - BackgroundPeople 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.MethodsBiological 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.FindingsBiological 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.InterpretationExplanation 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.FundingMain 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”.
UR - http://www.scopus.com/inward/record.url?scp=85166983572&partnerID=8YFLogxK
U2 - 10.1016/j.ebiom.2023.104692
DO - 10.1016/j.ebiom.2023.104692
M3 - Article
SN - 2352-3964
VL - 94
JO - EBioMedicine
JF - EBioMedicine
M1 - 104692
ER -