Dose imbalance of DYRK1A kinase causes systemic progeroid status in Down syndrome by increasing the un-repaired DNA damage and reducing LaminB1 levels

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

doi:10.1016/j.ebiom.2023.104692

Dose imbalance of DYRK1A kinase causes systemic progeroid status in Down syndrome by increasing the un-repaired DNA damage and reducing LaminB1 levels

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 YeapFrederic 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

Research output: Contribution to journal › Article › peer-review

Abstract

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. 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. 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. 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. 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". [Abstract copyright: Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.]

Original language	English
Pages (from-to)	104692
Journal	EBioMedicine
Early online date	5 Jul 2023
DOIs	https://doi.org/10.1016/j.ebiom.2023.104692
Publication status	E-pub ahead of print - 5 Jul 2023

Keywords

Ageing
Chromosome 21
DYRK1A
DYRK1A inhibitors
Down syndrome
Down syndrome critical region
IgG glycan
LaminB1

Access to Document

10.1016/j.ebiom.2023.104692

https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(23)00257-8/fulltext

Cite this

Murray, A., Gough, G., Cindrić, A., Vučković, F., Koschut, D., Borelli, V., Petrović, D. J., Bekavac, A., Plećaš, A., Hribljan, V., Brunmeir, R., Jurić, J., Pučić-Baković, M., Slana, A., Deriš, H., Frkatović, A., Groet, J., O'Brien, N. L., Chen, H. Y., ... Nižetić, D. (2023). Dose imbalance of DYRK1A kinase causes systemic progeroid status in Down syndrome by increasing the un-repaired DNA damage and reducing LaminB1 levels. EBioMedicine, 104692. Advance online publication. https://doi.org/10.1016/j.ebiom.2023.104692

@article{8496a3939b3a4e82b4da8a47c8b212ec,

title = "Dose imbalance of DYRK1A kinase causes systemic progeroid status in Down syndrome by increasing the un-repaired DNA damage and reducing LaminB1 levels",

abstract = "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. 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. 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. 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. 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{"}. [Abstract copyright: Copyright {\textcopyright} 2023 The Author(s). Published by Elsevier B.V. All rights reserved.]",

keywords = "Ageing, Chromosome 21, DYRK1A, DYRK1A inhibitors, Down syndrome, Down syndrome critical region, IgG glycan, LaminB1",

author = "Aoife Murray and Gillian Gough and Ana Cindri{\'c} and Frano Vu{\v c}kovi{\'c} and David Koschut and Vincenzo Borelli and Petrovi{\'c}, {Dra{\v z}en J} and Ana Bekavac and Ante Ple{\'c}a{\v s} and Valentina Hribljan and Reinhard Brunmeir and Julija Juri{\'c} and Maja Pu{\v c}i{\'c}-Bakovi{\'c} and Anita Slana and Helena Deri{\v s} and Azra Frkatovi{\'c} and J{\H u}rgen Groet and O'Brien, {Niamh L} and Chen, {Hong Yu} and Yeap, {Yee Jie} and Frederic Delom and Steven Havlicek and Luke Gammon and Sarah Hamburg and Carla Startin and Hana D'Souza and Dinko Mitre{\v c}i{\'c} and Mijana Kero and Ljubica Odak and Bo{\v z}o Kru{\v s}lin and {\v Z}eljka Krsnik and Ivica Kostovi{\'c} and Foo, {Jia Nee} and Yuin-Han Loh and Dunn, {Norris Ray} and {de la Luna}, Susana and Tim Spector and Ingeborg Bari{\v s}i{\'c} and Thomas, {Michael S C} and Andre Strydom and Claudio Franceschi and Gordan Lauc and Jasminka Kri{\v s}ti{\'c} and Ivan Ali{\'c} and Dean Ni{\v z}eti{\'c}",

year = "2023",

month = jul,

day = "5",

doi = "10.1016/j.ebiom.2023.104692",

language = "English",

pages = "104692",

journal = "EBioMedicine",

issn = "2352-3964",

publisher = "Elsevier",

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Murray, A, Gough, G, Cindrić, A, Vučković, F, Koschut, D, Borelli, V, Petrović, DJ, Bekavac, A, Plećaš, A, Hribljan, V, Brunmeir, R, Jurić, J, Pučić-Baković, M, Slana, A, Deriš, H, Frkatović, A, Groet, J, O'Brien, NL, Chen, HY, Yeap, YJ, Delom, F, Havlicek, S, Gammon, L, Hamburg, S, Startin, C, D'Souza, H, Mitrečić, D, Kero, M, Odak, L, Krušlin, B, Krsnik, Ž, Kostović, I, Foo, JN, Loh, Y-H, Dunn, NR, de la Luna, S, Spector, T, Barišić, I, Thomas, MSC, Strydom, A, Franceschi, C, Lauc, G, Krištić, J, Alić, I & Nižetić, D 2023, 'Dose imbalance of DYRK1A kinase causes systemic progeroid status in Down syndrome by increasing the un-repaired DNA damage and reducing LaminB1 levels', EBioMedicine, pp. 104692. https://doi.org/10.1016/j.ebiom.2023.104692

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 - Murray, Aoife

AU - Gough, Gillian

AU - Cindrić, Ana

AU - Vučković, Frano

AU - Koschut, David

AU - Borelli, Vincenzo

AU - Petrović, Dražen J

AU - Bekavac, Ana

AU - Plećaš, Ante

AU - Hribljan, Valentina

AU - Brunmeir, Reinhard

AU - Jurić, Julija

AU - Pučić-Baković, Maja

AU - Slana, Anita

AU - Deriš, Helena

AU - Frkatović, Azra

AU - Groet, Jűrgen

AU - O'Brien, Niamh L

AU - Chen, Hong Yu

AU - Yeap, Yee Jie

AU - Delom, Frederic

AU - Havlicek, Steven

AU - Gammon, Luke

AU - Hamburg, Sarah

AU - Startin, Carla

AU - D'Souza, Hana

AU - Mitrečić, Dinko

AU - Kero, Mijana

AU - Odak, Ljubica

AU - Krušlin, Božo

AU - Krsnik, Željka

AU - Kostović, Ivica

AU - Foo, Jia Nee

AU - Loh, Yuin-Han

AU - Dunn, Norris Ray

AU - de la Luna, Susana

AU - Spector, Tim

AU - Barišić, Ingeborg

AU - Thomas, Michael S C

AU - Strydom, Andre

AU - Franceschi, Claudio

AU - Lauc, Gordan

AU - Krištić, Jasminka

AU - Alić, Ivan

AU - Nižetić, Dean

PY - 2023/7/5

Y1 - 2023/7/5

N2 - 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. 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. 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. 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. 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". [Abstract copyright: Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.]

AB - 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. 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. 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. 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. 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". [Abstract copyright: Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.]

KW - Ageing

KW - Chromosome 21

KW - DYRK1A

KW - DYRK1A inhibitors

KW - Down syndrome

KW - Down syndrome critical region

KW - IgG glycan

KW - LaminB1

U2 - 10.1016/j.ebiom.2023.104692

DO - 10.1016/j.ebiom.2023.104692

M3 - Article

C2 - 37451904

SN - 2352-3964

SP - 104692

JO - EBioMedicine

JF - EBioMedicine

ER -