Targeting of NAT10 enhances healthspan in a mouse model of human accelerated aging syndrome.
Gabriel BalmusDelphine LarrieuAna C BarrosCasey CollinsMonica I AbrudanMukerrem DemirNicola J GeislerChristopher J LelliottJacqueline K WhiteNatasha A KarpJames AtkinsonAndrea KirtonMatthew JacobsenDean CliftRaphaël Rodrigueznull nullDavid J AdamsStephen P JacksonPublished in: Nature communications (2018)
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.
Keyphrases
- dna damage
- mouse model
- small molecule
- cardiovascular disease
- cancer therapy
- endothelial cells
- genome wide
- end stage renal disease
- electronic health record
- ejection fraction
- healthcare
- chronic kidney disease
- oxidative stress
- newly diagnosed
- gene expression
- mental health
- dna repair
- case report
- peritoneal dialysis
- dna methylation
- copy number
- protein protein
- patient reported outcomes
- bone marrow
- coronary artery disease
- cell therapy
- cardiovascular events
- stress induced