Lederer Eva-Maria, Fenzl Felix Quirin, Krüger Peter, Schroll Moritz, Hartinger Ramona, Djabali Karima
Epigenetics of Aging, Department of Dermatology and Allergy, TUM School of Medicine, Munich Institute of Biomedical Engineering (MIBE), Technical University of Munich (TUM), 85748 Garching, Germany.
Diseases. 2025 Aug 4;13(8):245. doi: 10.3390/diseases13080245.
BACKGROUND/OBJECTIVES: Hutchinson-Gilford progeria syndrome (HGPS) is a rare and fatal genetic disease caused by a silent mutation in the LMNA gene, leading to the production of progerin, a defective prelamin A variant. Progerin accumulation disrupts nuclear integrity, alters chromatin organization, and drives systemic cellular dysfunction. While autophagy and inflammation are key dysregulated pathways in HGPS, the role of microRNAs (miRNAs) in these processes remains poorly understood.
We performed an extensive literature review to identify miRNAs involved in autophagy and inflammation. Through stem-loop RT-qPCR in aging HGPS and control fibroblast strains, we identified significant miRNAs and focused on the most prominent one, miR-181a-5p, for in-depth analysis. We validated our in vitro findings with miRNA expression studies in skin biopsies from an HGPS mouse model and conducted functional assays in human fibroblasts, including immunofluorescence staining, β-Galactosidase assay, qPCR, and Western blot analysis. Transfection studies were performed using an miR-181a-5p mimic and its inhibitor.
We identified miR-181a-5p as a critical regulator of premature senescence in HGPS. miR-181a-5p was significantly upregulated in HGPS fibroblasts and an HGPS mouse model, correlating with Sirtuin 1 (SIRT1) suppression and induction of senescence. Additionally, we demonstrated that TGFβ1 induced miR-181a-5p expression, linking inflammation to miRNA-mediated senescence. Inhibiting miR-181a-5p restored SIRT1 levels, increased proliferation, and alleviated senescence in HGPS fibroblasts, supporting its functional relevance in disease progression.
These findings highlight the important role of miR-181a-5p in premature aging and suggest its potential as a therapeutic target for modulating senescence in progeroid syndromes.
背景/目的：哈钦森-吉尔福德早衰综合征（HGPS）是一种由LMNA基因沉默突变引起的罕见致命性遗传病，导致早老素的产生，早老素是一种有缺陷的前层粘连蛋白A变体。早老素的积累会破坏核完整性，改变染色质组织，并导致全身细胞功能障碍。虽然自噬和炎症是HGPS中关键的失调途径，但微小RNA（miRNA）在这些过程中的作用仍知之甚少。
我们进行了广泛的文献综述，以确定参与自噬和炎症的miRNA。通过对衰老的HGPS和成纤维细胞对照株进行茎环逆转录定量PCR，我们鉴定出了显著的miRNA，并聚焦于最突出的一种，即miR-181a-5p，进行深入分析。我们通过对HGPS小鼠模型皮肤活检的miRNA表达研究验证了体外研究结果，并在人成纤维细胞中进行了功能测定，包括免疫荧光染色、β-半乳糖苷酶测定、定量PCR和蛋白质印迹分析。使用miR-181a-5p模拟物及其抑制剂进行转染研究。
我们确定miR-181a-5p是HGPS过早衰老的关键调节因子。miR-181a-5p在HGPS成纤维细胞和HGPS小鼠模型中显著上调，与沉默调节蛋白1（SIRT1）的抑制和衰老诱导相关。此外，我们证明转化生长因子β1（TGFβ1）诱导miR-181a-5p表达，将炎症与miRNA介导的衰老联系起来。抑制miR-181a-5p可恢复HGPS成纤维细胞中SIRT1水平，增加细胞增殖并减轻衰老，支持其在疾病进展中的功能相关性。
这些发现突出了miR-181a-5p在过早衰老中的重要作用，并表明其作为调节早衰综合征衰老的治疗靶点的潜力。
