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
  • 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. [email protected].
  • 4. Department of Clinical Biochemistry, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 0XY, UK. [email protected].
  • 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. [email protected].
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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