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

Gabriel Balmus, Delphine Larrieu (), Ana C. Barros, Casey Collins, Monica Abrudan, Mukerrem Demir, Nicola J. Geisler, Christopher J. Lelliott, Jacqueline K. White, Natasha A. Karp, James Atkinson, Andrea Kirton, Matt Jacobsen, Dean Clift, Raphael Rodriguez, David J. Adams and Stephen P. Jackson ()
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Gabriel Balmus: University of Cambridge
Delphine Larrieu: University of Cambridge
Ana C. Barros: University of Cambridge
Casey Collins: The Wellcome Trust Sanger Institute, Hinxton
Monica Abrudan: The Wellcome Trust Sanger Institute, Hinxton
Mukerrem Demir: University of Cambridge
Nicola J. Geisler: University of Cambridge
Christopher J. Lelliott: The Wellcome Trust Sanger Institute, Hinxton
Jacqueline K. White: The Wellcome Trust Sanger Institute, Hinxton
Natasha A. Karp: The Wellcome Trust Sanger Institute, Hinxton
James Atkinson: AstraZeneca
Andrea Kirton: The Wellcome Trust Sanger Institute, Hinxton
Matt Jacobsen: AstraZeneca
Dean Clift: Laboratory of Molecular Biology
Raphael Rodriguez: PSL Research University
David J. Adams: The Wellcome Trust Sanger Institute, Hinxton
Stephen P. Jackson: University of Cambridge

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-03770-3

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