Assessing the efficacy of protein farnesyltransferase inhibitors in mouse models of progeria.
Assessing the efficacy of protein farnesyltransferase inhibitors in mouse models of progeria.
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DOI：
10.1194/jlr.m002808
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发表时间：
2010-02
影响因子：
6.5
通讯作者：
Fong LG
中科院分区：
文献类型：
--
作者：
Yang SH;Chang SY;Andres DA;Spielmann HP;Young SG;Fong LG
Hutchinson-Gilford早衰综合征（HGPS）是由前核层蛋白A（早老蛋白）的法尼基化形式的积累引起的。以前，我们表明，阻断蛋白法尼基化与法尼基转移酶抑制剂（FTI）改善HGPS（LmnaHG/+）的小鼠模型中的疾病表型。然而，FTI治疗研究的解释是开放的问题，鉴于最近的研究表明，小鼠表达的非法尼基化版本的早老蛋白（LmnanHG/+）发展早衰症样疾病表型。LmnaHG/+小鼠表现出疾病的事实提出了一种可能性，即FTI在LmnaHG/+小鼠中的有益作用不是由于药物对早老蛋白法尼基化的影响，而是由于药物对其他法尼基化蛋白的非预期继发性影响。为了解决这个问题，我们比较了FTI在LmnaHG/+和LmnanHG/+小鼠中改善早衰样疾病表型的能力。在LmnaHG/+小鼠中，FTI以非常显著的方式降低了疾病表型，但该药物在LmnaHG/+小鼠中没有作用。FTI未能改善LmnaHG/+小鼠中的疾病支持了FTI在LmnaHG/+小鼠中的有益作用是由于药物对早老蛋白的法尼基化的作用的观点。
Hutchinson-Gilford progeria syndrome (HGPS) is caused by the accumulation of a farnesylated form of prelamin A (progerin). Previously, we showed that blocking protein farnesylation with a farnesyltransferase inhibitor (FTI) ameliorates the disease phenotypes in mouse model of HGPS (LmnaHG/+). However, the interpretation of the FTI treatment studies is open to question in light of recent studies showing that mice expressing a nonfarnesylated version of progerin (LmnanHG/+) develop progeria-like disease phenotypes. The fact that LmnanHG/+ mice manifest disease raised the possibility that the beneficial effects of an FTI in LmnaHG/+ mice were not due to the effects of the drug on the farnesylation of progerin, but may have been due to unanticipated secondary effects of the drug on other farnesylated proteins. To address this issue, we compared the ability of an FTI to improve progeria-like disease phenotypes in both LmnaHG/+ and LmnanHG/+ mice. In LmnaHG/+ mice, the FTI reduced disease phenotypes in a highly significant manner, but the drug had no effect in LmnanHG/+ mice. The failure of the FTI to ameliorate disease in LmnanHG/+ mice supports the idea that the beneficial effects of an FTI in LmnaHG/+ mice are due to the effect of drug on the farnesylation of progerin.