prikaz prve stranice dokumenta Dose imbalance of DYRK1A kinase causes systemic progeroid status in Down syndrome by increasing the un-repaired DNA damage and reducing LaminB1 levels
  Download
PDF 4.32 MB
Scientific paper - Original scientific paper
Dose imbalance of DYRK1A kinase causes systemic progeroid status in Down syndrome by increasing the un-repaired DNA damage and reducing LaminB1 levels
eBioMedicine, 94 (2023); 104692. https://doi.org/10.1016/j.ebiom.2023.104692
Murray, Aoife; Gough, Gillian; Cindrić, Ana; Vučković, Frano; Koschut, David; Borelli, Vincenzo; Petrović, Dražen J.; Bekavac, Ana; Plećaš, Ante; Hribljan, Valentina; Brunmeir, Reinhard; Jurić, Julija; Pučić-Baković, Maja; Slana, Anita; Deriš, Helena; Frkatović, Azra; Groet, Jűrgen; O’Brien, Niamh L.; Chen, Hong Yu; Yeap, Yee Jie; Delom, Frederic; Havlicek, Steven; Gammon, Luke; Hamburg, Sarah; Startin, Carla; D’Souza, Hana; Mitrečić, Dinko; Kero, Mijana; Odak, Ljubica; Krušlin, Božo; Krsnik, Željka; Kostović, Ivica; Foo, Jia Nee; Loh, Yuin-Han; Dunn, Norris Ray; de la Luna, Susana; Spector, Tim; Barišić, Ingeborg; Thomas, Michael S.C.; Strydom, Andre; Franceschi, Claudio; Lauc, Gordan; Krištić, Jasminka; Alić, Ivan; Nižetić, Dean More authors...

Cite this document

Murray, A., Gough, G., Cindrić, A., Vučković, F., Koschut, D., Borelli, V. ... 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, 94.. doi: 10.1016/j.ebiom.2023.104692

Murray, Aoife, et al. "Dose imbalance of DYRK1A kinase causes systemic progeroid status in Down syndrome by increasing the un-repaired DNA damage and reducing LaminB1 levels." eBioMedicine, vol. 94, 2023. https://doi.org/10.1016/j.ebiom.2023.104692

Murray, Aoife, Gillian Gough, Ana Cindrić, Frano Vučković, David Koschut, Vincenzo Borelli, Dražen J. Petrović, et al. "Dose imbalance of DYRK1A kinase causes systemic progeroid status in Down syndrome by increasing the un-repaired DNA damage and reducing LaminB1 levels." eBioMedicine 94 (2023). https://doi.org/10.1016/j.ebiom.2023.104692

Murray, A., et al. (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, 94. doi: 10.1016/j.ebiom.2023.104692

Murray A, Gough G, Cindrić A, Vučković F, Koschut D, Borelli V, and sur.. Dose imbalance of DYRK1A kinase causes systemic progeroid status in Down syndrome by increasing the un-repaired DNA damage and reducing LaminB1 levels. eBioMedicine [Internet]. 2023 August [cited 2024 September 26];94. doi: 10.1016/j.ebiom.2023.104692

A. Murray, et al., "Dose imbalance of DYRK1A kinase causes systemic progeroid status in Down syndrome by increasing the un-repaired DNA damage and reducing LaminB1 levels", eBioMedicine, vol. 94, August 2023. [Online]. Available at: https://urn.nsk.hr/urn:nbn:hr:105:015489. [Accessed: 26 September 2024]

Please login to the repository to save this object to your list.
Metadata
Title (english)Dose imbalance of DYRK1A kinase causes systemic progeroid status in Down syndrome by increasing the un-repaired DNA damage and reducing LaminB1 levels
AuthorAoife Murray
AuthorGillian Gough
AuthorAna Cindrić
AuthorFrano Vučković
AuthorDavid Koschut
AuthorVincenzo Borelli
AuthorDražen J. Petrović
AuthorAna Bekavac
AuthorAnte Plećaš
AuthorValentina Hribljan
AuthorReinhard Brunmeir
AuthorJulija Jurić
AuthorMaja Pučić-Baković
AuthorAnita Slana
AuthorHelena Deriš
AuthorAzra Frkatović
AuthorJűrgen Groet
AuthorNiamh L. O’Brien
AuthorHong Yu Chen
AuthorYee Jie Yeap
AuthorFrederic Delom
AuthorSteven Havlicek
AuthorLuke Gammon
AuthorSarah Hamburg
AuthorCarla Startin
AuthorHana D’Souza
AuthorDinko Mitrečić
AuthorMijana Kero
AuthorLjubica Odak
AuthorBožo Krušlin
AuthorŽeljka Krsnik
AuthorIvica Kostović
AuthorJia Nee Foo
AuthorYuin-Han Loh
AuthorNorris Ray Dunn
AuthorSusana de la Luna
AuthorTim Spector
AuthorIngeborg Barišić
AuthorMichael S.C. Thomas
AuthorAndre Strydom
AuthorClaudio Franceschi
AuthorGordan Lauc
AuthorJasminka Krištić
AuthorIvan Alić
AuthorDean Nižetić
Author's institutionUniversity of Zagreb
School of Medicine
(Croatian Institiute for Brain Research)
Author's institutionUniversity of Zagreb
School of Medicine
(Department of Histology and Embryology)
Author's institutionUniversity of Zagreb
School of Medicine
(Department of Pathology)
Scientific / art field,
discipline and subdiscipline		BIOMEDICINE AND HEALTHCARE
Basic Medical Sciences
Cytology, Histology and Embryology
Scientific / art field,
discipline and subdiscipline		BIOMEDICINE AND HEALTHCARE
Clinical Medical Sciences
Pathology
Abstract (english)
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.
Keywords (english)
Languageenglish
Publication typeScientific paper - Original scientific paper
Publication statusPublished
Peer reviewPeer review
Publication versionPublished version
Journal titleeBioMedicine
Numberingvol. 94, 104692
p-ISSN2352-3964
DOIhttps://doi.org/10.1016/j.ebiom.2023.104692
URN:NBNurn:nbn:hr:105:015489
Publication2023-08
Document URLhttps://linkinghub.elsevier.com/retrieve/pii/S2352396423002578
Type of resourceText
Access conditionsOpen access
Terms of useLicence Attribution 4.0 International (CC BY 4.0) icon
Created on2024-09-25 11:19:53