CLC-3 deficiency leads to phenotypes similar to human neuronal ceroid lipofuscinosis
CLC-3 deficiency leads to phenotypes similar to human neuronal ceroid lipofuscinosis
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DOI：
10.1046/j.1365-2443.2002.00539.x
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发表时间：
2002-06-01
期刊：
影响因子：
2.1
通讯作者：
Sasaki, S
中科院分区：
文献类型：
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作者：
Yoshikawa, M;Uchida, S;Sasaki, S
背景：CLC-3是CLC氯离子通道家族的成员，在哺乳动物组织中广泛表达。结果：CLC-3（-/-）小鼠表现为失明、运动协调障碍和自发性过度运动等神经系统表现，并伴有发育迟缓和较高的死亡率。在组织学分析中，Clcn 3（-/-）小鼠显示视网膜、海马和回肠粘膜的进行性变性模式，其类似于在组织蛋白酶D敲除小鼠中观察到的表型。组织蛋白酶D的缺陷导致含有线粒体F1 F0 ATP酶亚基c的蜡样脂褐素在溶酶体中积聚。免疫组化和Western blot分析发现，C1 cn 3（-/-）小鼠的溶酶体中有大量c亚基的积累。此外，我们检测到的Clcn 3（-/-）mice.Conclusions内体pH值的升高：这些结果表明，在Clcn 3（-/-）小鼠中观察到的神经退行性变是由异常的机器，降解细胞蛋白质，并与神经元蜡样脂褐质沉积症（NCL）的表型。内体pH升高可能是NCL发病的重要因素。
Background: CLC-3 is a member of the CLC chloride channel family and is widely expressed in mammalian tissues. To determine the physiological role of CLC-3, we generated CLC-3-deficient mice (Clcn3(-/-)) by targeted gene disrupt-ion.Results: Together with developmental retardation and higher mortality, the Clcn3(-/-) mice showed neurological manifestations such as blindness, motor coordination deficit, and spontaneous hyperlocomotion. In histological analysis, the Clcn3(-/-) mice showed a pattern of progressive degeneration of the retina, hippocampus and ileal mucosa, which resembled the phenotype observed in cathepsin D knockout mice. The defect of cathepsin D results in a lysosomal accumulation of ceroid lipofuscin containing the mitochondrial F1F0 ATPase subunit c. In immunohistochemistry and Western blot analysis, we found that the subunit c was heavily accumulated in the lysosome of Clcn3(-/-) mice. Furthermore, we detected an elevation in the endosomal pH of the Clcn3(-/-) mice.Conclusions: These results indicated that the neurodegeneration observed in the Clcn3(-/-) mice was caused by an abnormality in the machinery which degrades the cellular protein and was associated with the phenotype of neuronal ceroid lipofuscinosis (NCL). The elevated endosomal pH could be an important factor in the pathogenesis of NCL.