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.
Sanford Burnham Prebys Medical Discovery Institute, 10901 N Torrey Pines Rd, La Jolla, CA 92037, USA.
Int J Mol Sci. 2024 Aug 28;25(17):9323. doi: 10.3390/ijms25179323.
Hutchinson-Gilford Progeria Syndrome (HGPS) is an extremely rare genetic disorder that causes accelerated aging, due to a pathogenic variant in the LMNA gene. This pathogenic results in the production of progerin, a defective protein that disrupts the nuclear lamina's structure. In our study, we conducted a histopathological analysis of various organs in the Lmna mouse model, which is commonly used to study HGPS. The objective of this study was to show that progerin accumulation drives systemic but organ-specific tissue damage and accelerated aging phenotypes. Our findings show significant fibrosis, inflammation, and dysfunction in multiple organ systems, including the skin, cardiovascular system, muscles, lungs, liver, kidneys, spleen, thymus, and heart. Specifically, we observed severe vascular fibrosis, reduced muscle regeneration, lung tissue remodeling, depletion of fat in the liver, and disruptions in immune structures. These results underscore the systemic nature of the disease and suggest that chronic inflammation and fibrosis play crucial roles in the accelerated aging seen in HGPS. Additionally, our study highlights that each organ responds differently to the toxic effects of progerin, indicating that there are distinct mechanisms of tissue-specific damage.
亨廷顿舞蹈病-吉福德早衰综合征（HGPS）是一种极为罕见的遗传疾病，由于 LMNA 基因的致病性变异，导致加速衰老。这种致病性导致前病毒的产生，前病毒是一种有缺陷的蛋白质，破坏核纤层的结构。在我们的研究中，我们对常用于研究 HGPS 的 Lmna 小鼠模型的各种器官进行了组织病理学分析。本研究的目的是表明前病毒的积累会导致全身性但器官特异性的组织损伤和加速衰老表型。我们的研究结果表明，多个器官系统（包括皮肤、心血管系统、肌肉、肺、肝、肾、脾、胸腺和心脏）出现显著的纤维化、炎症和功能障碍。具体来说，我们观察到严重的血管纤维化、肌肉再生减少、肺组织重塑、肝脏脂肪耗竭以及免疫结构破坏。这些结果强调了该疾病的全身性，并表明慢性炎症和纤维化在 HGPS 中观察到的加速衰老中起着关键作用。此外，我们的研究表明，每个器官对前病毒的毒性作用有不同的反应，表明存在组织特异性损伤的独特机制。
