Targeting of NAT10 enhances healthspan in a mouse model of human accelerated aging syndrome.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 29703891.
- Also identified by DOI 10.1038/s41467-018-03770-3 and PMC identifier 5923383.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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 <sup>G609G</sup> HGPS mouse model. Collectively, the data provided here highlights NAT10 as a potential therapeutic target for HGPS.
Medical subject headings
- Aging, Premature
- Genomic Instability
- Hydrazones
- N-Terminal Acetyltransferase A
- Progeria
- Thiazoles