2. Academic Validation
  3. Targeting of NAT10 enhances healthspan in a mouse model of human accelerated aging syndrome

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

  • Nat Commun. 2018 Apr 27;9(1):1700. doi: 10.1038/s41467-018-03770-3.
Gabriel Balmus 1 2,  Delphine Larrieu 3 4,  Ana C Barros 1 2,  Casey Collins 2,  Monica Abrudan 2,  Mukerrem Demir 1,  Nicola J Geisler 1 2,  Christopher J Lelliott 2,  Jacqueline K White 2,  Natasha A Karp 2 5,  James Atkinson 6,  Andrea Kirton 2,  Matt Jacobsen 6,  Dean Clift 7,  Raphael Rodriguez 8 9 10,  Sanger Mouse Genetics Project,   David J Adams 2,  Stephen P Jackson 11
Affiliations

Affiliations

  • 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.
PMID: 29703891 DOI: 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.

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