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

被引：158

作者：

Balmus, Gabriel ^{[1
,2
,3
]}

Larrieu, Delphine ^{[1
,2
,10
]}

Barros, Ana C. ^{[1
,2
,3
]}

Collins, Casey ^{[3
]}

Abrudan, Monica ^{[3
]}

Demir, Mukerrem ^{[1
,2
]}

Geisler, Nicola J. ^{[1
,2
,3
]}

Lelliott, Christopher J. ^{[3
]}

White, Jacqueline K. ^{[3
]}

Karp, Natasha A. ^{[3
,4
]}

Atkinson, James ^{[5
]}

Kirton, Andrea ^{[3
]}

Jacobsen, Matt ^{[5
]}

Clift, Dean ^{[6
]}

Rodriguez, Raphael ^{[7
,8
,9
]}

Adams, David J. ^{[3
]}

Jackson, Stephen P. ^{[1
,2
]}

机构：

[1] Univ Cambridge, Canc Res UK Gurdon Inst, Wellcome Trust, Cambridge CB2 1QN, England

[2] Univ Cambridge, Dept Biochem, Cambridge CB2 1QN, England

[3] Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England

[4] AstraZeneca, IMED Biotech Unit, Discovery Sci, Cambridge CB4 0WG, England

[5] AstraZeneca, IMED Biotech Unit, Drug Safety & Metab, Cambridge CB2 23AT, England

[6] Lab Mol Biol, Cambridge CB2 OQH, England

[7] PSL Res Univ, Inst Curie, Paris 05, France

[8] CNRS, UMR3666, F-75005 Paris, France

[9] INSERM, U1143, F-75005 Paris, France

[10] Univ Cambridge, Cambridge Inst Med Res, Dept Clin Biochem, Cambridge CB2 0XY, England

来源：

NATURE COMMUNICATIONS | 2018年 / 9卷

基金：

英国惠康基金; 英国医学研究理事会; 欧洲研究理事会;

关键词：

GILFORD PROGERIA SYNDROME; GENOME-WIDE; NUCLEAR-ENVELOPE; GENE-EXPRESSION; KNOCKOUT MICE; LAMIN-A; PROTEIN; FARNESYLATION; BIOCONDUCTOR; FIBROBLASTS;

D O I：

10.1038/s41467-018-03770-3

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

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.

引用

页数：14

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