Mice deficient in the Vici syndrome gene Epg5 exhibit features of retinitis pigmentosa
Mice deficient in the Vici syndrome gene Epg5 exhibit features of retinitis pigmentosa
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Vici综合征基因Epg5缺陷的小鼠表现出色素性视网膜炎的特征
DOI：
10.1080/15548627.2016.1238554
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发表时间：
2016-01-01
期刊：
影响因子：
13.3
通讯作者：
Zhang, Hong
中科院分区：
文献类型：
--
作者：
Miao, Guangyan;Zhao, Yan G.;Zhang, Hong
摘要自噬通过去除错误折叠的蛋白质和受损的细胞器来帮助维持细胞的动态平衡，通常是神经元存活的一种细胞保护机制。在这里，我们显示了缺乏Vici综合征基因Epg5的小鼠，这是自噬体成熟所必需的，在不同类型的视网膜细胞中显示出泛素阳性包涵体和SQSTM1聚集体的积累。在EPG5−/−视网膜中，光感受器功能严重受损，外核层感光细胞数量逐渐减少和凋亡细胞数量增加等变性特征，而视网膜其他部分的形态没有受到严重影响。在epg5−/−视网膜中，未折叠蛋白反应(UPR)的下游靶点，包括死亡诱导因子DDIT3/CHOP，以及裂解的CASP3(Caspase3)的水平都升高。因此，EPG5−/−视网膜光感受器细胞的凋亡性死亡可能是由于UPR升高所致。我们的结果表明EPG5基因缺陷的小鼠概括了视网膜色素变性的关键特征，因此可能为研究光感受器退化的分子机制提供一个有价值的模型。
ABSTRACT Autophagy helps to maintain cellular homeostasis by removing misfolded proteins and damaged organelles, and generally acts as a cytoprotective mechanism for neuronal survival. Here we showed that mice deficient in the Vici syndrome gene Epg5, which is required for autophagosome maturation, show accumulation of ubiquitin-positive inclusions and SQSTM1 aggregates in various retinal cell types. In epg5−/− retinas, photoreceptor function is greatly impaired, and degenerative features including progressively reduced numbers of photoreceptor cells and increased numbers of apoptotic cells in the outer nuclear layer are observed, while the morphology of other parts of the retina is not severely affected. Downstream targets of the unfolded protein response (UPR), including the death inducer DDIT3/CHOP, and also levels of cleaved CASP3 (caspase 3), are elevated in epg5−/− retinas. Thus, apoptotic photoreceptor cell death in epg5−/− retinas may result from the elevated UPR. Our results reveal that Epg5-deficient mice recapitulate key characteristics of retinitis pigmentosa and thus may provide a valuable model for investigating the molecular mechanism of photoreceptor degeneration.