Sano Yae, Furuta Akiko, Setsuie Rieko, Kikuchi Hisae, Wang Yu-Lai, Sakurai Mikako, Kwon Jungkee, Noda Mami, Wada Keiji
Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1, Ogawahigashi, Kodaira, Tokyo 187-8502, Japan.
Am J Pathol. 2006 Jul;169(1):132-41. doi: 10.2353/ajpath.2006.060085.
UCH-L3 belongs to the ubiquitin C-terminal hydrolase family that deubiquitinates ubiquitin-protein conjugates in the ubiquitin-proteasome system. A murine Uchl3 deletion mutant displays retinal degeneration, muscular degeneration, and mild growth retardation. To elucidate the function of UCH-L3, we investigated histopathological changes and expression of apoptosis- and oxidative stress-related proteins during retinal degeneration. In the normal retina, UCH-L3 was enriched in the photoreceptor inner segment that contains abundant mitochondria. Although the retina of Uchl3-deficient mice showed no significant morphological abnormalities during retinal development, prominent retinal degeneration became manifested after 3 weeks of age associated with photoreceptor cell apoptosis. Ultrastructurally, a decreased area of mitochondrial cristae and vacuolar changes were observed in the degenerated inner segment. Increased immunoreactivities for manganese superoxide dismutase, cytochrome c oxidase I, and apoptosis-inducing factor in the inner segment indicated mitochondrial oxidative stress. Expression of cytochrome c, caspase-1, and cleaved caspase-3 did not differ between wild-type and mutant mice; however, immunoreactivity for endonuclease G was found in the photoreceptor nuclei in the mutant retina. Hence, loss of UCH-L3 leads to mitochondrial oxidative stress-related photoreceptor cell apoptosis in a caspase-independent manner. Thus, Uchl3-deficient mice represent a model for adult-onset retinal degeneration associated with mitochondrial impairment.
UCH-L3属于泛素C末端水解酶家族，在泛素-蛋白酶体系统中使泛素-蛋白质缀合物去泛素化。一种小鼠Uchl3缺失突变体表现出视网膜变性、肌肉变性和轻度生长迟缓。为了阐明UCH-L3的功能，我们研究了视网膜变性过程中的组织病理学变化以及凋亡和氧化应激相关蛋白的表达。在正常视网膜中，UCH-L3富集于含有丰富线粒体的光感受器内段。尽管Uchl3基因缺陷小鼠的视网膜在视网膜发育过程中未显示出明显的形态学异常，但在3周龄后与光感受器细胞凋亡相关的明显视网膜变性开始显现。超微结构上，在变性的内段观察到线粒体嵴面积减小和空泡变化。内段中锰超氧化物歧化酶、细胞色素c氧化酶I和凋亡诱导因子的免疫反应性增加表明存在线粒体氧化应激。野生型和突变型小鼠之间细胞色素c、半胱天冬酶-1和裂解的半胱天冬酶-3的表达没有差异；然而，在突变型视网膜的光感受器细胞核中发现了核酸内切酶G的免疫反应性。因此，UCH-L3的缺失以半胱天冬酶非依赖性方式导致与线粒体氧化应激相关的光感受器细胞凋亡。因此，Uchl3基因缺陷小鼠代表了一种与线粒体损伤相关的成人发病型视网膜变性模型。
