From immature lamin to premature aging -: Molecular pathways and therapeutic opportunities
From immature lamin to premature aging -: Molecular pathways and therapeutic opportunities
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DOI：
10.4161/cc.4.12.2202
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发表时间：
2005-12-01
期刊：
影响因子：
4.3
通讯作者：
Freije, JMP
中科院分区：
文献类型：
--
作者：
Cadiñanos, J;Varela, I;Freije, JMP
加速衰老或早衰症多年来一直是一个令人困惑的疾病。最近的发现涉及层状蛋白A/FACE-1（底物/蛋白酶）系统在Hutchinson-Gilford早衰综合征的病因学和相关病理，揭示了这些破坏性疾病发展的潜在机制。因此，核包膜蛋白prelamin A或参与prelamin A蛋白水解成熟的FACE-1金属蛋白酶（也称为Zmspte24）中的遗传缺陷导致该蛋白异常形式的积累，并随后破坏核膜完整性。最近，我们和其他人已经观察到这种破坏如何导致染色质组织的改变、基因组不稳定、转录变化和p53相关信号通路的激活。通过在小鼠中使用遗传操作方法，我们已经证明降低prelamin A水平导致zmpste24缺陷小鼠从加速衰老过程中完全恢复。此外，p53的无合子性允许适度但显著的改善早衰表型，并有助于延迟早老性疾病的发作。在这些结果的基础上，我们提出了不同的潜在治疗方法，可以在zmpste24缺陷小鼠中进行测试。这些策略，其中一些是基于现有的药物，可能有助于开发有效的治疗这些戏剧性的病理。
Accelerated aging or progeria has been a puzzling disease for many years. The recent findings involving the lamin A/FACE-1 (substrate/protease) system in the etiology of Hutchinson-Gilford progeria syndrome and related pathologies have shed some light on the mechanisms underlying the development of these devastating conditions. Thus, genetic defects in the nuclear envelope protein prelamin A or in the FACE-1 metalloprotease ( also called Zmspte24) involved in prelamin A proteolytic maturation, cause the accumulation of an abnormal form of this protein and the subsequent disruption of nuclear envelope integrity. Recently, we and others have observed how this disruption leads to alterations in chromatin organization, genomic instability, transcriptional changes, and activation of a p53-linked signaling pathway. By using genetic manipulation approaches in mouse, we have shown that lowering prelamin A levels results in a total recovery of Zmpste24-deficient mice from the accelerated aging process. Moreover, p53 nullizygosity allows a modest but significant improvement in the premature aging phenotype, and contributes to delaying the onset of the progeroid condition. On the basis of these results, we propose different potential therapeutic approaches that could be tested in Zmpste24-deficient mice. These strategies, some of which are based on existing drugs, might contribute to the development of effective treatments for these dramatic pathologies.