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Published March 7, 2018 | Version v1
Journal article Open

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

  • 1. The Wellcome Trust/Cancer Research UK Gurdon Institute
  • 2. The Wellcome Trust Sanger Institute
  • 3. Discovery Sciences, IMED Biotech Unit, AstraZeneca
  • 4. Drug Safety and Metabolism, IMED Biotech Unit, AstraZeneca
  • 5. Laboratory of Molecular Biology, Cambridge
  • 6. Institut Curie, PSL Research University, Paris

Description

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 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 preclinical data demonstrating that targeting NAT10 in vivo, either via chemical inhibition or genetic depletion, significantly enhances cardiac function, fitness and healthspan in a LmnaG609G HGPS mouse model. Collectively, the data provided here highlight NAT10 as a potential therapeutic target for HGPS.

Notes

This data is presented in a Nature communications paper: NCOMMS-17-24850A Two folders are included, one for each gene that was analysed in the primary phenotyping pipeline. The RMD file is the R Markdown file for the analysis of each gene. The package "PhenStat" should be installed from Bioconductor. This dataset was analysed using Phenstat version 2.6.0. Other packages required are "tidyr", "plyr", "dplyr" and "MESS" for calculation of weight AUC. https://www.bioconductor.org/packages/release/bioc/html/PhenStat.html File names starting "catResults" are the Phenstat output for categorical variables File names starting "contResults" are the Phenstat output for continuous variables The Html in each folder is the Html version of the R Markdown file Raw or derived csv files contain the raw data tables used for the analysis. The gene that is tested is included in the file name.

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10.5281/zenodo.1193262 (DOI)