Nuclear damages and oxidative stress: new perspectives for laminopathies.
Nuclear damages and oxidative stress: new perspectives for laminopathies.
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DOI：
10.4081/ejh.2012.e45
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发表时间：
2012-10-18
期刊：
影响因子：
--
通讯作者：
Maraldi NM
中科院分区：
文献类型：
--
作者：
Lattanzi G;Marmiroli S;Facchini A;Maraldi NM
编码核膜蛋白，特别是编码A型核纤层蛋白的LMNA的基因突变引起广泛的多种疾病，称为核纤层蛋白病。令人惊讶的疾病表型的多样性表明，不同的机制可能参与了核纤层蛋白病的发病机制。在这篇综述中，我们将主要集中在这些致病机制中的两个：影响染色质组织的核损伤和氧化应激导致不可修复的DNA损伤。在细胞经历过早衰老的系统性核纤层蛋白病中，核轮廓和染色质组织的改变尤其令人印象深刻，这主要是由于未加工的前核纤层蛋白A的积累。这些干扰染色质相关蛋白、转录因子和信号传导途径的分子种类的毒性作用可以通过降低其法尼基化和/或稳定性的药物来降低。特别是，法尼基转移酶（FTI）的抑制剂已被证明在挽救改变的细胞表型中是有效的，并且他汀类药物也与其他药物联合，已被纳入试点临床试验。由于在核纤层病细胞中产生活性氧（ROS），导致不可修复的DNA损伤积累的机制的鉴定，类似于在由细胞外基质（ECM）组分的表达改变引起的其他肌营养不良症（MD）中发现的机制，表明抗氧化剂治疗策略可能证明对核纤层病患者有益。
Mutations in genes encoding nuclear envelope proteins, particularly LMNA encoding the A-type lamins, cause a broad range of diverse diseases, referred to as laminopathies. The astonishing variety of diseased phenotypes suggests that different mechanisms could be involved in the pathogenesis of laminopathies. In this review we will focus mainly on two of these pathogenic mechanisms: the nuclear damages affecting the chromatin organization, and the oxidative stress causing un-repairable DNA damages. Alteration in the nuclear profile and in chromatin organization, which are particularly impressive in systemic laminopathies whose cells undergo premature senescence, are mainly due to accumulation of unprocessed prelamin A. The toxic effect of these molecular species, which interfere with chromatin-associated proteins, transcription factors, and signaling pathways, could be reduced by drugs which reduce their farnesylation and/or stability. In particular, inhibitors of farnesyl transferase (FTIs), have been proved to be active in rescuing the altered cellular phenotype, and statins, also in association with other drugs, have been included into pilot clinical trials. The identification of a mechanism that accounts for accumulation of unrepairable DNA damage due to reactive oxygen species (ROS) generation in laminopathic cells, similar to that found in other muscular dystrophies (MDs) caused by altered expression of extracellular matrix (ECM) components, suggests that anti-oxidant therapeutic strategies might prove beneficial to laminopathic patients.
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影响因子：
8
作者：
Columbaro, M;Capanni, C;Mattioli, E;Novelli, G;Parnaik, VK;Squarzoni, S;Maraldi, NM;Lattanzi, G
通讯作者：
Lattanzi, G
影响因子：
11.4
作者：
Gonzalez-Suarez, Ignacio;Redwood, Abena B.;Gonzalo, Susana
通讯作者：
Gonzalo, Susana
影响因子：
4.6
作者：
Filesi, I;Gullotta, F;Novelli, G
通讯作者：
Novelli, G
影响因子：
3.5
作者：
De Vos, Winnok H.;Houben, Frederik;Broers, Jos L. V.
通讯作者：
Broers, Jos L. V.
影响因子：
3.5
作者：
Arimura, T;Helbling-Leclerc, A;Bonne, G
通讯作者：
Bonne, G