Griveau Audrey, Wiel Clotilde, Ziegler Dorian V, Bergo Martin O, Bernard David
Centre de Recherche en Cancérologie de Lyon, Inserm U1052, CNRS UMR 5286, Centre Léon Bérard, Université de Lyon, Lyon, France.
Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.
Aging Cell. 2020 Apr;19(4):e13122. doi: 10.1111/acel.13122. Epub 2020 Mar 20.
Hutchinson-Gilford progeria syndrome (HGPS) is caused by an LMNA mutation that results in the production of the abnormal progerin protein. Children with HGPS display phenotypes of premature aging and have an average lifespan of 13 years. We found earlier that the targeting of the transmembrane protein PLA2R1 overcomes senescence and improves phenotypes in a mouse model of progeria. PLA2R1 is regulating the JAK/STAT signaling, but we do not yet know whether targeting this pathway directly would influence cellular and in vivo progeria phenotypes. Here, we show that JAK1/2 inhibition with ruxolitinib rescues progerin-induced cell cycle arrest, cellular senescence, and misshapen nuclei in human normal fibroblasts expressing progerin. Moreover, ruxolitinib administration reduces several premature aging phenotypes: bone fractures, bone mineral content, grip strength, and a trend to increase survival in a mouse model of progeria. Thus, we propose that ruxolitinib, an FDA-approved drug, should be further evaluated as a drug candidate in HGPS therapy.
哈钦森-吉尔福德早衰综合征（HGPS）由一种LMNA突变引起，该突变导致异常的早老蛋白产生。患有HGPS的儿童表现出早衰的表型，平均寿命为13岁。我们之前发现，靶向跨膜蛋白PLA2R1可克服早衰，并改善早衰小鼠模型的表型。PLA2R1调节JAK/STAT信号传导，但我们尚不清楚直接靶向该信号通路是否会影响细胞和体内早衰表型。在此，我们表明，用鲁索替尼抑制JAK1/2可挽救早老蛋白诱导的人正常成纤维细胞中的细胞周期停滞、细胞衰老和细胞核畸形。此外，在早衰小鼠模型中，给予鲁索替尼可减轻几种早衰表型：骨折、骨矿物质含量、握力，并呈现出提高存活率的趋势。因此，我们建议，鲁索替尼这种已获美国食品药品监督管理局批准的药物，应作为治疗HGPS的候选药物进行进一步评估。
