Genetic reduction of mTOR extends lifespan in a mouse model of Hutchinson-Gilford Progeria syndrome.
Genetic reduction of mTOR extends lifespan in a mouse model of Hutchinson-Gilford Progeria syndrome.
复制标题
DOI：
10.1111/acel.13457
复制
发表时间：
2021-09
期刊：
影响因子：
7.8
通讯作者：
Collins FS
中科院分区：
文献类型：
--
作者：
Cabral WA;Tavarez UL;Beeram I;Yeritsyan D;Boku YD;Eckhaus MA;Nazarian A;Erdos MR;Collins FS
哈钦森-吉尔福德早老综合征（HGPS）是一种罕见的加速衰老疾病，最显著的特征是心血管疾病和心肌梗死或中风导致的过早死亡。大多数病例是由LMNA基因中的从头单核苷酸突变引起的，该突变激活隐蔽剪接供体位点，导致产生具有50个氨基酸内部缺失的核纤层蛋白A的毒性形式，称为早老蛋白。我们先前报道了一种携带人类BAC的早衰症转基因小鼠模型的产生，该BAC携带常见突变G608 G，其在单拷贝状态下发展出仅限于血管系统的HGPS特征。在这里，我们报告的表型小鼠饲养携带两个副本的BAC，更完整地概括了HGPS在皮肤，脂肪，骨骼和血管组织的表型特征。我们进一步表明，雷帕霉素（mTOR）的机制靶点的遗传减少显着延长这些小鼠的寿命，提供了一个基本原理的药理学抑制mTOR途径在治疗HGPS。在人类序列的背景下表达突变基因产物的动物模型的产生对于开发治疗HGPS的新治疗方法至关重要。在这里，我们表明，转基因小鼠窝藏两个拷贝的人LMNA基因含有G608 G突变重演的人类表型。这些小鼠中mTOR的遗传减少延长了寿命，并为临床试验测试HGPS患者中mTOR信号通路的药理学抑制提供了理论基础。
Hutchinson‐Gilford progeria syndrome (HGPS) is a rare accelerated aging disorder most notably characterized by cardiovascular disease and premature death from myocardial infarction or stroke. The majority of cases are caused by a de novo single nucleotide mutation in the LMNA gene that activates a cryptic splice donor site, resulting in production of a toxic form of lamin A with a 50 amino acid internal deletion, termed progerin. We previously reported the generation of a transgenic murine model of progeria carrying a human BAC harboring the common mutation, G608G, which in the single‐copy state develops features of HGPS that are limited to the vascular system. Here, we report the phenotype of mice bred to carry two copies of the BAC, which more completely recapitulate the phenotypic features of HGPS in skin, adipose, skeletal, and vascular tissues. We further show that genetic reduction of the mechanistic target of rapamycin (mTOR) significantly extends lifespan in these mice, providing a rationale for pharmacologic inhibition of the mTOR pathway in the treatment of HGPS. Generation of animal models that express the mutant gene product in the context of the human sequence is critical for developing novel therapeutic approaches to treat HGPS. Here we show that transgenic mice harboring two copies of the human LMNA gene containing the G608G mutation recapitulate the human phenotype. Genetic reduction of mTOR in these mice extends lifespan and provides a rationale for clinical trials testing pharmacological inhibition of the mTOR signaling pathway in HGPS patients.
登录
查看更多内容
影响因子：
--
作者：
Kinoshita D;Nagasawa A;Shimizu I;Ito TK;Yoshida Y;Tsuchida M;Iwama A;Hayano T;Minamino T
通讯作者：
Minamino T
DOI：
10.1073/pnas.1906713117
发表时间：
2020-06-02
影响因子：
11.1
作者：
Cubria, Maria B.;Suarez, Sebastian;Nazarian, Ara
通讯作者：
Nazarian, Ara
影响因子：
17.1
作者：
Osorio, Fernando G.;Navarro, Claire L.;Lopez-Otin, Carlos
通讯作者：
Lopez-Otin, Carlos
影响因子：
17.1
作者：
Cao, Kan;Graziotto, John J.;Collins, Francis S.
通讯作者：
Collins, Francis S.
影响因子：
11.1
作者：
Hamczyk, Magda R.;Villa-Bellosta, Ricardo;Andres, Vicente
通讯作者：
Andres, Vicente