核层蛋白A前体的法尼基化与衰老  

Relationship between Farnesylation of prelamin A and aging

作　　者：袁源[1,2,3] 陈维春[1,2,3] 刘新光[1,2,3] 周中军[4] 

机构地区：[1]广东省医学分子诊断重点实验室,东莞523808 [2]广东医学院衰老研究所,东莞523808 [3]广东医学院生物化学与分子生物学研究所,湛江524023 [4]香港大学李嘉诚医学院生物化学系,香港999077

出　　处：《生命的化学》2011年第4期592-597,共6页Chemistry of Life

基　　金：国家自然科学基金(30672205308714403090073930971620);广东省自然科学基金(730150684524023010014509252402301000002);广东省高等学校自然科学研究重点项目(06Z015);湛江市科技局招标项目(ZZ0605);东莞市科技计划项目(20081081010452008108101062)资助

摘　　要：编码核层蛋白A(lamin A)的LMNA基因突变导致法尼基化的核层蛋白A前体(prelamin A)不能被进一步加工成成熟的核层蛋白A,从而导致一种Hutchinson-Gilford早老症综合征(Hutchinson-Gilford progeria syndrome,HGPS)。一种更严重的早老症——限制性皮肤病(restrictive dermopathy,RD),是由于缺失核层蛋白A前体加工过程中的剪切酶ZMPSTE24引起的。ZMPSTE24的缺失阻止了法尼基化的核层蛋白A前体不能正常加工成为成熟的核层蛋白A,同时导致法尼基化的核层蛋白A前体的堆积。在HGPS和RD病人的成纤维细胞中,发现法尼基化的核层蛋白A前体都定位在核膜,从而影响细胞核膜的完整性,并导致细胞核形的异常,进而导致衰老。最近研究表明经过法尼基酰转移酶抑制剂(farnesyltransferase inhibitor,FTI)处理后的细胞的核形异常减少。同时,FTI能够改善HGPS和RD小鼠的早老症状。本文就核层蛋白A前体的法尼基化对衰老的影响有关研究进展作一综述。Specific mutation in LMNA gives rise to a truncated prelamin A called progerin leading to Hutchinson-Gilford progeria syndrome(HGPS).A more severe progeroid disorder,restrictive dermopathy(RD),is caused by the loss of the prelamin A-processing enzyme,ZMPSTE24.The absence of ZMPSTE24 prevents the endoproteolytic processing of farnesyl-prelamin A to mature lamin A and leads to the accumulation of farnesyl-prelamin A.In both HGPS and RD,the farnesyl-prelamin A is targeted to the nuclear envelope,where it interferes with the integrity of the nuclear envelope and causes misshapen cell nuclei,resulting in cellular senescence.Recent studies have shown that the frequency of misshapen nuclei can be reduced by treating cells with a farnesyltransferase inhibitor(FTI).Also,administering an FTI to mouse models of HGPS and RD ameliorates the phenotypes of progeria.This paper summarizes the advance in study on the contribution of prelamin A farnesylation to premature aging.

关 键 词：Hutchinson-Gilford早老症综合征(HGPS) 核层蛋白A前体 法尼基化 法尼基酰转移酶抑制剂 

分 类 号：Q51[生物学—生物化学]