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

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.

Authors:: G Balmus, D Larrieu, AC Barros, C Collins, M Abrudan, M Demir, NJ Geisler, CJ Lelliott, JK White, NA Karp, J Atkinson, A Kirton, M Jacobsen, D Clift, R Rodriguez, Sanger Mouse Genetics Project, DJ Adams, SP Jackson

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