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Nat Commun. 2018 Apr 27;9(1):1700. doi: 10.1038/s41467-018-03770-3.

Targeting of NAT10 enhances healthspan in a mouse model of human accelerated aging syndrome.

Author information

1
The Wellcome Trust/Cancer Research UK Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge, CB2 1QN, UK.
2
The Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK.
3
The Wellcome Trust/Cancer Research UK Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge, CB2 1QN, UK. dl437@cam.ac.uk.
4
Department of Clinical Biochemistry, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 0XY, UK. dl437@cam.ac.uk.
5
Discovery Sciences, IMED Biotech Unit, AstraZeneca, Cambridge, CB4 0WG, UK.
6
Drug Safety and Metabolism, IMED Biotech Unit, AstraZeneca, Cambridge, CB2 23AT, UK.
7
Laboratory of Molecular Biology, Cambridge, CB2 OQH, UK.
8
Institut Curie, PSL Research University, Paris Cedex 05, France.
9
CNRS UMR3666, 75005, Paris, France.
10
INSERM U1143, 75005, Paris, France.
11
The Wellcome Trust/Cancer Research UK Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge, CB2 1QN, UK. s.jackson@gurdon.cam.ac.uk.

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.

PMID:
29703891
PMCID:
PMC5923383
DOI:
10.1038/s41467-018-03770-3
[Indexed for MEDLINE]
Free PMC Article

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