Hutchinson-Gilford Progeria Syndrome: Challenges at Bench and Bedside.
Hutchinson-Gilford Progeria Syndrome: Challenges at Bench and Bedside.
复制标题
DOI：
10.1007/978-981-13-3681-2_15
复制
发表时间：
2019-01-01
影响因子：
--
通讯作者：
Gonzalo, Susana
中科院分区：
文献类型：
--
作者：
Kreienkamp, Ray;Gonzalo, Susana
被称为“层蛋白”的结构核蛋白（a型和b型）为基因组功能的区隔化提供了一个支架，这对维持基因组的稳定性很重要。编码a型纤层蛋白的LMNA基因突变与十几种被称为纤层病的退行性疾病有关，其中包括肌肉营养不良症、脂肪营养不良症、神经病变和早衰疾病，如哈金森-吉尔福德早衰综合征（HGPS）。这种毁灭性的疾病是由一种被称为“progerin”的截短的层状蛋白a的表达引起的。迄今为止，对于青少年时期死于心血管疾病的HGPS患者，尚无有效的治疗方法。在细胞水平上，早衰蛋白的表达影响核结构、染色质组织、对机械应力的反应以及转录、复制和修复等DNA交易。然而，目前的观点是，早衰蛋白毒性背后的关键机制仍有待发现。在这里，我们讨论了关于HGPS病理机制的新发现，特别是复制应激对细胞衰退的贡献，以及改善早衰蛋白毒性的治疗策略。特别是，我们提出了类维生素a和骨化三醇（激素维生素D代谢物）是体外改善HGPS细胞表型最有效的化合物之一的证据，为近期在疾病的临床前模型和未来的患者中测试这些化合物提供了理论依据。
The structural nuclear proteins known as "lamins" (A-type and B-type) provide a scaffold for the compartmentalization of genome function that is important to maintain genome stability. Mutations in the LMNA gene -encoding for A-type lamins- are associated with over a dozen of degenerative disorders termed laminopathies, which include muscular dystrophies, lipodystrophies, neuropathies, and premature ageing diseases such as Hutchinson Gilford Progeria Syndrome (HGPS). This devastating disease is caused by the expression of a truncated lamin A protein named "progerin". To date, there is no effective treatment for HGPS patients, who die in their teens from cardiovascular disease. At a cellular level, progerin expression impacts nuclear architecture, chromatin organization, response to mechanical stress, and DNA transactions such as transcription, replication and repair. However, the current view is that key mechanisms behind progerin toxicity still remain to be discovered. Here, we discuss new findings about pathological mechanisms in HGPS, especially the contribution of replication stress to cellular decline, and therapeutic strategies to ameliorate progerin toxicity. In particular, we present evidence for retinoids and calcitriol (hormonal vitamin D metabolite) being among the most potent compounds to ameliorate HGPS cellular phenotypes in vitro, providing the rationale for testing these compounds in preclinical models of the disease in the near term, and in patients in the future.