Department of Molecular Biology, Pusan National University, Busan, Republic of Korea.
Program in Food Science and Biotechnology, College of Agriculture and Life Sciences, Seoul National University, Seoul, Republic of Korea.
Sci Rep. 2021 Apr 27;11(1):9122. doi: 10.1038/s41598-021-88325-1.
Werner syndrome (WRN) is a rare progressive genetic disorder, caused by functional defects in WRN protein and RecQ4L DNA helicase. Acceleration of the aging process is initiated at puberty and the expected life span is approximately the late 50 s. However, a Wrn-deficient mouse model does not show premature aging phenotypes or a short life span, implying that aging processes differ greatly between humans and mice. Gene expression analysis of WRN cells reveals very similar results to gene expression analysis of Hutchinson Gilford progeria syndrome (HGPS) cells, suggesting that these human progeroid syndromes share a common pathological mechanism. Here we show that WRN cells also express progerin, an abnormal variant of the lamin A protein. In addition, we reveal that duplicated sequences of human WRN (hWRN) from exon 9 to exon 10, which differ from the sequence of mouse WRN (mWRN), are a natural inhibitor of progerin. Overexpression of hWRN reduced progerin expression and aging features in HGPS cells. Furthermore, the elimination of progerin by siRNA or a progerin-inhibitor (SLC-D011 also called progerinin) can ameliorate senescence phenotypes in WRN fibroblasts and cardiomyocytes, derived from WRN-iPSCs. These results suggest that progerin, which easily accumulates under WRN-deficient conditions, can lead to premature aging in WRN and that this effect can be prevented by SLC-D011.
Werner 综合征（WRN）是一种罕见的进行性遗传疾病，由 WRN 蛋白和 RecQ4L DNA 解旋酶的功能缺陷引起。衰老过程的加速始于青春期，预期寿命约为 50 多岁后期。然而，Wrn 缺陷型小鼠模型并未表现出早衰表型或寿命缩短，这表明人类和小鼠的衰老过程有很大差异。WRN 细胞的基因表达分析与 Hutchinson-Gilford 早衰综合征（HGPS）细胞的基因表达分析非常相似，表明这些人类早衰综合征具有共同的病理机制。在这里，我们表明 WRN 细胞还表达了核纤层蛋白 A 的异常变体——早衰蛋白。此外，我们揭示了人 WRN（hWRN）从外显子 9 到外显子 10 的重复序列，与鼠 WRN（mWRN）的序列不同，是早衰蛋白的天然抑制剂。hWRN 的过表达降低了 HGPS 细胞中早衰蛋白的表达和衰老特征。此外，siRNA 或一种早衰蛋白抑制剂（SLC-D011，也称为 progerinin）消除早衰蛋白可以改善 WRN 成纤维细胞和心肌细胞的衰老表型，这些细胞来自 WRN-iPSCs。这些结果表明，在 WRN 缺陷条件下容易积累的早衰蛋白可能导致 WRN 早衰，而 SLC-D011 可以预防这种效应。
