Targeting of NAT10 enhances healthspan in a mouse model of human accelerated aging syndrome.
Targeting of NAT10 enhances healthspan in a mouse model of human accelerated aging syndrome.
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DOI：
10.1038/s41467-018-03770-3
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发表时间：
2018-04-27
影响因子：
16.6
通讯作者：
Jackson SP
中科院分区：
文献类型：
--
作者：
Balmus G;Larrieu D;Barros AC;Collins C;Abrudan M;Demir M;Geisler NJ;Lelliott CJ;White JK;Karp NA;Atkinson J;Kirton A;Jacobsen M;Clift D;Rodriguez R;Sanger Mouse Genetics Project;Adams DJ;Jackson SP
Hutchinson-Gilford早衰综合征（HGPS）是一种罕见但具有破坏性的遗传性疾病，其特征是节段性过早衰老，心血管疾病是死亡的主要原因。来自HGPS患者的细胞积累早老蛋白，一种永久法尼基化的核纤层蛋白A的毒性形式，破坏核形状和染色质组织，导致DNA损伤积累和衰老。靶向法尼基化或旨在降低早老蛋白水平的治疗方法仅提供了部分健康改善。最近，我们确定了Remodelin，一种小分子药物，通过抑制N-乙酰转移酶10（NAT 10）来改善HGPS细胞缺陷。在这里，我们展示了临床前数据，证明通过化学抑制或遗传耗竭在体内靶向NAT 10，显著增强了LmnaG 609 G HGPS小鼠模型的健康寿命。总的来说，这里提供的数据突出了NAT 10作为HGPS的潜在治疗靶点。Hutchinson-Gilford早衰综合征的特征是过早衰老，心血管疾病是死亡的主要原因。在这里，作者表明，抑制NAT 10酶可以增强心脏功能和健康，并减少过早衰老小鼠模型中与年龄相关的表型。
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 LmnaG609G HGPS mouse model. Collectively, the data provided here highlights NAT10 as a potential therapeutic target for HGPS. Hutchinson-Gilford Progeria Syndrome is characterized by premature aging with cardiovascular disease being the main cause of death. Here the authors show that inhibition of the NAT10 enzyme enhances cardiac function and fitness, and reduces age-related phenotypes in a mouse model of premature aging.
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影响因子：
64.5
作者：
López-Otín C;Blasco MA;Partridge L;Serrano M;Kroemer G
通讯作者：
Kroemer G
影响因子：
3.7
作者：
Karp NA;Speak AO;White JK;Adams DJ;Hrabé de Angelis M;Hérault Y;Mott RF
通讯作者：
Mott RF
影响因子：
9
作者：
Blondel S;Egesipe AL;Picardi P;Jaskowiak AL;Notarnicola M;Ragot J;Tournois J;Le Corf A;Brinon B;Poydenot P;Georges P;Navarro C;Pitrez PR;Ferreira L;Bollot G;Bauvais C;Laustriat D;Mejat A;De Sandre-Giovannoli A;Levy N;Bifulco M;Peschanski M;Nissan X
通讯作者：
Nissan X
影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J
影响因子：
3.7
作者：
Karp NA;Melvin D;Sanger Mouse Genetics Project;Mott RF
通讯作者：
Mott RF