Zmpste24基因缺失与早老症

Zmpste24 Deficiency and Progeria

衰老是一种生理完整性丧失,功能受损,疾病和死亡风险增加的过程。早老症(HGPS)是一种加速化的衰老疾病,是研究人类正常衰老理想的疾病模型。由LMNA基因突变产生prelamin AΔ50在细胞内累积是造成早老症的主要原因,早老症病人表现出寿命急剧缩短,老化特征明显的现象,例如脱发、皮下脂肪减少、骨质疏松以及早逝。锌金属蛋白酶Zmpste24是prelamin A加工成为成熟lamin A蛋白的关键酶。敲除Zmpste24基因的小鼠表现出与早老症高度一致的衰老表型,同时也存在非常相似的发病机制,如染色质异常、DNA损伤和干细胞功能缺失等。Zmpste24缺失小鼠作为典型的早老模型小鼠因其衰老周期短,衰老特征明显而获得广泛应用。本文总结了以Zmpste24缺失早老小鼠为模型取得的早老相关分子机制的研究进展,以及抗衰老策略的最新发现。

Ageing is a progressive process associated with loss of physiological integrity, impaired functions and increased vulnerability to death. Human ageing research has benefited from the study of Hutchinson-Gilford progeria syndrome （HGPS） , an accelerated premature ageing disorder due to nuclear lamin A mutation. A specific mutation in LMNA gene gives rise to an alternative spliced variant known as progerin or prelaminAas leading to HGPS. HGPS patients manifest accelerated ageing symptoms including alopecia,loss of subcutaneous fat, growth retardation, atherosclerosis and premature death. Zinc- metalloprotease Zmpste24 is one of key enzymes processing prelamin A to mature lamin A. Depletion of Zmpste24 in mice recapitulates HGPS and exhibits similar progeroid symptoms found in HGPS patients. Zmpste24-deficiency mouse model has been widely used for aging study. Mechanistically they share paralleled molecular defects such as chromatin disorganization, increased DNA damages, stem cell decline, etc. This review summarized the recent findings in Zmpste24-deficiency mice.