Targeting of NAT10 enhances healthspan in a mouse model of human accelerated aging syndrome.
Authors
Barros, Ana C
Demir, Mukerrem
Geisler, Nicola J
White, Jacqueline K
Karp, Natasha A
Kirton, Andrea
Clift, Dean
Sanger Mouse Genetics Project
Adams, David J
Publication Date
2018-04-27Journal Title
Nat Commun
ISSN
2041-1723
Publisher
Springer Science and Business Media LLC
Volume
9
Issue
1
Pages
1700
Language
eng
Type
Article
This Version
AM
Physical Medium
Electronic
Metadata
Show full item recordCitation
Balmus, G., Larrieu, D., Barros, A. C., Collins, C., Abrudan, M., Demir, M., Geisler, N. J., et al. (2018). Targeting of NAT10 enhances healthspan in a mouse model of human accelerated aging syndrome.. Nat Commun, 9 (1), 1700. https://doi.org/10.1038/s41467-018-03770-3
Abstract
Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare, but devastating genetic disease characterized by segmental premature aging, with cardiovascular disease being the main cause of death. Cells from HGPS patients accumulate progerin, a permanently farnesylated, toxic form of Lamin A, disrupting the nuclear shape and chromatin organization, leading to DNA-damage accumulation and senescence. Therapeutic approaches targeting farnesylation or aiming to reduce progerin levels have provided only partial health improvements. Recently, we identified Remodelin, a small-molecule agent that leads to amelioration of HGPS cellular defects through inhibition of the enzyme N-acetyltransferase 10 (NAT10). Here, we show the preclinical data demonstrating that targeting NAT10 in vivo, either via chemical inhibition or genetic depletion, significantly enhances the healthspan in a Lmna G609G HGPS mouse model. Collectively, the data provided here highlights NAT10 as a potential therapeutic target for HGPS.
Keywords
Sanger Mouse Genetics Project, Animals, Mice, Inbred C57BL, Mice, Knockout, Humans, Mice, Progeria, DNA Damage, Disease Models, Animal, Genomic Instability, Aging, Premature, Hydrazones, Thiazoles, Lamin Type A, Female, Male, Kaplan-Meier Estimate, N-Terminal Acetyltransferase A, N-Terminal Acetyltransferases
Sponsorship
Cancer Research Uk (None)
Medical Research Council (MR/L019116/1)
Cancer Research UK (18796)
Wellcome Trust (206388/Z/17/Z)
Cancer Research UK (C6946/A24843)
Wellcome Trust (203144/Z/16/Z)
Embargo Lift Date
2100-01-01
Identifiers
External DOI: https://doi.org/10.1038/s41467-018-03770-3
This record's URL: https://www.repository.cam.ac.uk/handle/1810/271873
Rights
Licence:
http://creativecommons.org/licenses/by/4.0/
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