Targeting of NAT10 enhances healthspan in a mouse model of human accelerated aging syndrome
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Balmus, Gabriel | Larrieu, Delphine | Barros, Ana | Collins, Casey | Abrudan, Monica | Demir, Mukerrem | Geisler, Nicola | Lelliott, Christopher | White, Jacqueline | Karp, Natasha | Atkinson, James | Kirton, Andrea | Jacobsen, Matt | Clift, Dean | Rodriguez, Raphael | Shannon, Carl | Sanderson, Mark | Gates, Amy | Dench, Joshua | Vancollie, Valerie | Mccarthy, Catherine | Pearson, Selina | Cambridge, Emma | Isherwood, Christopher | Wilson, Heather | Grau, Evelyn | Galli, Antonella | Hooks, Yvette | Tudor, Catherine | Green, Angela | Kussy, Fiona | Tuck, Elizabeth | Siragher, Emma | Mclaren, Robbie | Swiatkowska, Agnieszka | Caetano, Susana | Mazzeo, Cecilia Icoresi | Dabrowska, Monika | Maguire, Simon | Lafont, David | Anthony, Lauren | Sumowski, Maksymilian | Bussell, James | Sinclair, Caroline | Brown, Ellen | Doe, Brendan | Wardle-Jones, Hannah | Griggs, Nicola | Woods, Mike | Kundi, Helen | Mcconnell, George | Doran, Joanne | Griffiths, Mark | Kipp, Christian | Holroyd, Simon | Gannon, David | Alcantara, Rafael | Bottomley, Joanna | Ingle, Catherine | Ross, Victoria | Barrett, Daniel | Sethi, Debarati | Gleeson, Diane | Burvill, Jonathan | Platte, Radka | Ryder, Edward | Sins, Elodie | Miklejewska, Evelina | von Schiller, Dominique | Duddy, Graham | Urbanova, Jana | Boroviak, Katharina | Imran, Maria | Reddy, Shalini Kamu | Adams, David | Jackson, Stephen
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CCSD ; Nature Publishing Group -
International audience.
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.
