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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Blocking protein farnesyltransferase improves nuclear shape in fibroblasts from humans with progeroid syndromes
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Blocking protein farnesyltransferase improves nuclear shape in fibroblasts from humans with progeroid syndromes

机译：阻断蛋白法尼基转移酶改善患有早衰综合症的人的成纤维细胞的核形状

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摘要

Defects in the biogenesis of lamin A from its farnesylated precursor, prelamin A, lead to the accumulation of prelamin A at the nuclear envelope, cause misshapen nuclei, and result in progeroid syndromes. A deficiency in ZMPSTE24, a protease involved in prelamin A processing, leads to prelamin A accumulation, an absence of mature lamin A, misshapen nuclei, and a lethal perinatal progeroid syndrome: restrictive dermopathy (RD). Hutchinson-Gilford progeria syndrome (HGPS) is caused by a mutant prelamin A that cannot be processed to lamin A. The hallmark cellular abnormality in RD and HGPS is misshapen nuclei. We hypothesized that the farnesylation of prelamin A is important for its targeting to the nuclear envelope in RD and HGPS and that blocking farnesylation would ameliorate the nuclear shape abnormalities. Indeed, when RD fibroblasts were treated with a farnesyltransferase inhibitor (FTI), prelamin A was partially mislocalized away from the nuclear envelope, and the frequency of nuclear shape abnormalities was reduced (P < 0.0001). A FTI also mislocalized prelamin A and improved nuclear shape in Zmpste24-deficient mouse embryonic fibroblasts (P < 0.0001) and improved nuclear shape in human HGPS fibroblasts (P < 0.0001). Most remarkably, a FTI significantly improved nuclear shape in two fibroblast cell lines from atypical progeria patients with lamin A missense mutations in the absence of prelamin A accumulation (P = 0.0003 and P < 0.0001). These findings establish a paradigm for ameliorating the most obvious cellular pathology in lamin-related progeroid syndromes and suggest a potential strategy for treating these diseases.
机译：层粘连蛋白A的法呢基化前体prelamin A的生物合成缺陷，导致prelamin A积聚在核被膜上，引起畸形的核，并导致早衰综合征。 ZMPSTE24（参与prelamin A加工的蛋白酶）的缺乏会导致prelamin A积聚，不存在成熟的层粘蛋白A，核畸形和致命的围产期早孕综合症：限制性皮肤病（RD）。 Hutchinson-Gilford早衰综合症（HGPS）由无法处理为层粘连蛋白A的突变型预蛋白A引起。RD和HGPS中标志性的细胞异常是细胞核畸形。我们假设，前醇溶蛋白A的法尼基化对其靶向RD和HGPS的核膜很重要，而阻断法尼基化可改善核形状异常。确实，当用法呢基转移酶抑制剂（FTI）处理RD成纤维细胞时，预纤蛋白A局部错位远离核膜，核形状异常的频率降低了（P <0.0001）。 FTI还使prelamin A定位错误，并改善了Zmpste24缺陷型小鼠胚胎成纤维细胞的核形（P <0.0001），并改善了人类HGPS成纤维细胞的核形（P <0.0001）。最显着的是，FTI显着改善了在不存在纤溶酶原A积累的情况下，具有层粘连蛋白A错义突变的非典型早衰患者的两个成纤维细胞系的核形（P = 0.0003和P <0.0001）。这些发现建立了改善与椎板相关的早老症候群中最明显的细胞病理学的范例，并提出了治疗这些疾病的潜在策略。

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