Prelamin A and ZMPSTE24 in premature and physiological aging.
Prelamin A and ZMPSTE24 in premature and physiological aging.
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DOI：
10.1080/19491034.2023.2270345
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发表时间：
2023-12
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影响因子：
--
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随着人类寿命的延长，了解导致衰老的分子机制对于促进健康和预防与年龄相关的疾病变得越来越重要。过早衰老疾病或早衰综合症可以为生理衰老的各个方面提供重要的见解。 LMNA 和 ZMPSTE24 基因突变导致早衰综合症的一个主要原因是核支架蛋白核纤层蛋白 A 产生过程中最终翻译后加工步骤的破坏。LMNA 编码核纤层蛋白 A 前体、前核纤层蛋白 A，而 ZMPSTE24 编码前核纤层蛋白 A 加工酶、锌金属蛋白酶 ZMPSTE24。这些基因突变引起的早衰综合征包括临床相关疾病哈钦森-吉尔福德早衰综合征 (HGPS)、B 型下颌骨发育不良和限制性皮肤病。这些疾病具有相互重叠的特征以及与生理衰老的某些方面重叠的特征，包括类似于骨质疏松症和动脉粥样硬化的骨缺陷（后者主要发生在 HGPS）。早衰综合症引发了人们对有缺陷的前核蛋白 A 加工与其在正常生理衰老中积累之间关系的浓厚兴趣。在这篇综述中，我们研究了这样的假设：ZMPSTE24 对前核纤层蛋白 A 的加工减少是生理衰老的驱动因素。我们回顾了一种新小鼠 (LmnaL648R/L648R)，它只产生未经加工的前核纤层蛋白 A，并为检查其在衰老过程中积累的影响提供了理想的模型。我们还讨论了有关人类生理衰老中 prelamin A 或其变体积累的现有数据，这些数据需要进一步验证和更严格的实验方法来确定 prelamin A 是否有助于正常衰老。
As human longevity increases, understanding the molecular mechanisms that drive aging becomes ever more critical to promote health and prevent age-related disorders. Premature aging disorders or progeroid syndromes can provide critical insights into aspects of physiological aging. A major cause of progeroid syndromes which result from mutations in the genes LMNA and ZMPSTE24 is disruption of the final posttranslational processing step in the production of the nuclear scaffold protein lamin A. LMNA encodes the lamin A precursor, prelamin A and ZMPSTE24 encodes the prelamin A processing enzyme, the zinc metalloprotease ZMPSTE24. Progeroid syndromes resulting from mutations in these genes include the clinically related disorders Hutchinson–Gilford progeria syndrome (HGPS), mandibuloacral dysplasia-type B, and restrictive dermopathy. These diseases have features that overlap with one another and with some aspects of physiological aging, including bone defects resembling osteoporosis and atherosclerosis (the latter primarily in HGPS). The progeroid syndromes have ignited keen interest in the relationship between defective prelamin A processing and its accumulation in normal physiological aging. In this review, we examine the hypothesis that diminished processing of prelamin A by ZMPSTE24 is a driver of physiological aging. We review features a new mouse (LmnaL648R/L648R) that produces solely unprocessed prelamin A and provides an ideal model for examining the effects of its accumulation during aging. We also discuss existing data on the accumulation of prelamin A or its variants in human physiological aging, which call out for further validation and more rigorous experimental approaches to determine if prelamin A contributes to normal aging.
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发表时间：
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影响因子：
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