Targeting of NAT10 enhances healthspan in a mouse model of human accelerated aging syndrome
Creators
- Balmus, Gabriel1
- Larrieu, Delphine1
- Barros, Ana1
- Collins, Casey2
- Abrudan, Monica2
- Demir, Mukerrem1
- Geisler, Nicola1
- Lelliott, Christopher2
- White, Jacqueline2
- Karp, Natasha3
- Atkinson, James4
- Kirton, Andrea2
- Jacobsen, Matt4
- Clift, Dean5
- Sanger Mouse Genetics Project2
- Rodriguez, Raphael6
- Adams, David2
- Jackson, Stephen1
- 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.
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Related works
- Is documented by
- 10.5281/zenodo.1193262 (DOI)