Gonzalez Jose M, Pla Davinia, Perez-Sala Dolores, Andres Vicente
Department of Molecular and Cellular Pathology and Therapy, Instituto de Biomedicina de Valencia, Consejo Superior de Investigaciones Cientificas (CSIC), Valencia, Spain.
Front Biosci (Schol Ed). 2011 Jun 1;3(3):1133-46. doi: 10.2741/216.
Lamin A and lamin C (A-type lamins, both encoded by the LMNA gene) are major components of the mammalian nuclear lamina, a complex proteinaceous structure that acts as a scaffold for protein complexes that regulate nuclear structure and function. Abnormal accumulation of farnesylated-progerin, a mutant form of prelamin A, plays a key role in the pathogenesis of the Hutchinson-Gilford progeria syndrome (HGPS), a devastating disorder that causes the death of affected children at an average age of 13.5 years, predominantly from premature atherosclerosis and myocardial infarction or stroke. Remarkably, progerin is also present in normal cells and appears to progressively accumulate during aging of non-HGPS cells. Therefore, understanding how this mutant form of lamin A provokes HGPS may shed significant insight into physiological aging. In this review, we discuss recent advances into the pathogenic mechanisms underlying HGPS, the main murine models of the disease, and the therapeutic strategies developed in cellular and animal models with the aim of reducing the accumulation of farnesylated-progerin, as well as their use in clinical trials of HGPS.
核纤层蛋白A和核纤层蛋白C（A型核纤层蛋白，均由LMNA基因编码）是哺乳动物核纤层的主要成分，核纤层是一种复杂的蛋白质结构，作为调节核结构和功能的蛋白质复合物的支架。法尼基化早衰蛋白（前体核纤层蛋白A的一种突变形式）的异常积累在哈钦森-吉尔福德早衰综合征（HGPS）的发病机制中起关键作用，HGPS是一种严重的疾病，导致受影响儿童平均在13.5岁死亡，主要死因是过早出现动脉粥样硬化、心肌梗死或中风。值得注意的是，早衰蛋白也存在于正常细胞中，并且在非HGPS细胞衰老过程中似乎会逐渐积累。因此，了解这种核纤层蛋白A的突变形式如何引发HGPS可能会为生理性衰老提供重要见解。在这篇综述中，我们讨论了HGPS潜在致病机制的最新进展、该疾病的主要小鼠模型，以及在细胞和动物模型中为减少法尼基化早衰蛋白积累而开发的治疗策略，以及它们在HGPS临床试验中的应用。
