Yang Shao H, Bergo Martin O, Toth Julia I, Qiao Xin, Hu Yan, Sandoval Salemiz, Meta Margarita, Bendale Pravin, Gelb Michael H, Young Stephen G, Fong Loren G
Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
Proc Natl Acad Sci U S A. 2005 Jul 19;102(29):10291-6. doi: 10.1073/pnas.0504641102. Epub 2005 Jul 12.
Hutchinson-Gilford progeria syndrome (HGPS), a progeroid syndrome in children, is caused by mutations in LMNA (the gene for prelamin A and lamin C) that result in the deletion of 50 aa within prelamin A. In normal cells, prelamin A is a "CAAX protein" that is farnesylated and then processed further to generate mature lamin A, which is a structural protein of the nuclear lamina. The mutant prelamin A in HGPS, which is commonly called progerin, retains the CAAX motif that triggers farnesylation, but the 50-aa deletion prevents the subsequent processing to mature lamin A. The presence of progerin adversely affects the integrity of the nuclear lamina, resulting in misshapen nuclei and nuclear blebs. We hypothesized that interfering with protein farnesylation would block the targeting of progerin to the nuclear envelope, and we further hypothesized that the mislocalization of progerin away from the nuclear envelope would improve the nuclear blebbing phenotype. To approach this hypothesis, we created a gene-targeted mouse model of HGPS, generated genetically identical primary mouse embryonic fibroblasts, and we then examined the effect of a farnesyltransferase inhibitor on nuclear blebbing. The farnesyltransferase inhibitor mislocalized progerin away from the nuclear envelope to the nucleoplasm, as determined by immunofluoresence microscopy, and resulted in a striking improvement in nuclear blebbing (P < 0.0001 by chi2 statistic). These studies suggest a possible treatment strategy for HGPS.
哈钦森-吉尔福德早衰综合征（HGPS）是一种儿童早衰症，由LMNA基因（前体核纤层蛋白A和核纤层蛋白C的基因）突变引起，该突变导致前体核纤层蛋白A内50个氨基酸缺失。在正常细胞中，前体核纤层蛋白A是一种“CAAX蛋白”，会被法尼基化，然后进一步加工生成成熟的核纤层蛋白A，它是核纤层的一种结构蛋白。HGPS中的突变前体核纤层蛋白A，通常称为早老素，保留了触发法尼基化的CAAX基序，但50个氨基酸的缺失阻止了后续加工成成熟的核纤层蛋白A。早老素的存在对核纤层的完整性产生不利影响，导致细胞核畸形和核泡形成。我们假设干扰蛋白质法尼基化会阻止早老素靶向核膜，并且我们进一步假设早老素从核膜的错误定位会改善核泡表型。为了验证这一假设，我们创建了一个HGPS的基因靶向小鼠模型，生成了基因相同的原代小鼠胚胎成纤维细胞，然后我们研究了法尼基转移酶抑制剂对核泡形成的影响。通过免疫荧光显微镜观察，法尼基转移酶抑制剂使早老素从核膜错误定位到核质中，并导致核泡形成显著改善（卡方检验P < 0.0001）。这些研究提示了一种可能的HGPS治疗策略。
