Grupo de Terapia Celular y Medicina Regenerativa, Departamento de Fisioterapia, Ciencias Biomédicas y Medicina, Universdidade da Coruña, Agrupación Estratégica INIBIC-CICA, 15006 A Coruña, Spain.
Int J Mol Sci. 2021 Jul 7;22(14):7327. doi: 10.3390/ijms22147327.
Hutchinson-Gilford progeria syndrome (HGPS) is a deadly childhood disorder, which is considered a very rare disease. It is caused by an autosomal dominant mutation on the LMNA gene, and it is characterized by accelerated aging. Human cell lines from HGPS patients and healthy parental controls were studied in parallel using next-generation sequencing (NGS) to unravel new non-previously altered molecular pathways. Nine hundred and eleven transcripts were differentially expressed when comparing healthy versus HGPS cell lines from a total of 21,872 transcripts; ITPR1, ITPR3, CACNA2D1, and CAMK2N1 stood out among them due to their links with calcium signaling, and these were validated by Western blot analysis. It was observed that the basal concentration of intracellular Ca was statistically higher in HGPS cell lines compared to healthy ones. The relationship between genes involved in Ca signaling and mitochondria-associated membranes (MAM) was demonstrated through cytosolic calcium handling by means of an automated fluorescent plate reading system (FlexStation 3, Molecular Devices), and apoptosis and mitochondrial ROS production were examined by means of flow cytometry analysis. Altogether, our data suggest that the Ca signaling pathway is altered in HGPS at least in part due to the overproduction of reactive oxygen species (ROS). Our results unravel a new therapeutic window for the treatment of this rare disease and open new strategies to study pathologies involving both accelerated and healthy aging.
亨廷顿舞蹈病-早老综合征（HGPS）是一种致命的儿童疾病，被认为是一种非常罕见的疾病。它是由 LMNA 基因突变引起的，其特征是衰老加速。使用下一代测序（NGS）平行研究 HGPS 患者和健康父母对照的人类细胞系，以揭示新的非先前改变的分子途径。在总共 21872 个转录本中，比较健康与 HGPS 细胞系时，有 911 个转录本表达差异；由于它们与钙信号的联系，ITPR1、ITPR3、CACNA2D1 和 CAMK2N1 脱颖而出，这些通过 Western blot 分析得到验证。观察到 HGPS 细胞系的细胞内 Ca 基础浓度与健康细胞系相比统计学上更高。通过自动荧光板读数系统（FlexStation 3，Molecular Devices）进行细胞质钙处理，证明了参与 Ca 信号和线粒体相关膜（MAM）的基因之间的关系，并通过流式细胞术分析检查了细胞凋亡和线粒体 ROS 的产生。总的来说，我们的数据表明，Ca 信号通路在 HGPS 中至少部分发生改变，这至少部分是由于活性氧（ROS）的过度产生。我们的结果为治疗这种罕见疾病开辟了一个新的治疗窗口，并为研究涉及加速和健康衰老的病理学开辟了新的策略。
