Lysosomal storage disease upon disruption of the neuronal chloride transport protein CIC-6
Lysosomal storage disease upon disruption of the neuronal chloride transport protein CIC-6
复制标题
DOI：
10.1073/pnas.0606137103
复制
发表时间：
2006-09-12
影响因子：
11.1
通讯作者：
Jentsch, Thomas J.
中科院分区：
文献类型：
--
作者：
Poet, Mallorie;Kornak, Uwe;Jentsch, Thomas J.
哺乳动物CLC蛋白作为Cl-通道或作为产电Cl-/H+交换剂起作用，并且存在于质膜和细胞内囊泡中。我们现在表明，ClC-6蛋白几乎只在中枢和外周神经系统的神经元中表达，在背根神经节中表达特别高。ClC-6与神经元细胞体中晚期内体的标记物共定位。小鼠中ClC-6的破坏降低了它们的疼痛敏感性，并导致中度行为异常。神经元组织在起始轴突节段显示自发荧光。在这些网站上，电子显微镜显示电子致密的存储材料，导致近端轴突的病理性扩大。这些沉积物对几种溶酶体蛋白和神经元蜡样脂褐质沉积症（NCL）（一种溶酶体沉积病）的典型标志物蛋白呈阳性。而Clcn 6（-/-）神经元的溶酶体pH值正常。CLCN 6是人类轻度NCL的候选基因。对75名NCL患者的分析在两名患者中鉴定了ClC-6氨基酸交换，但未能证明CLCN 6在该疾病中的致病作用。
Mammalian CLC proteins function as Cl- channels or as electrogenic Cl-/H+ exchangers and are present in the plasma membrane and intracellular vesicles. We now show that the ClC-6 protein is almost exclusively expressed in neurons of the central and peripheral nervous systems, with a particularly high expression in dorsal root ganglia. ClC-6 colocalized with markers for late endosomes in neuronal cell bodies. The disruption of ClC-6 in mice reduced their pain sensitivity and caused moderate behavioral abnormalities. Neuronal tissues showed autofluorescence at initial axon segments. At these sites, electron microscopy revealed electron-dense storage material that caused a pathological enlargement of proximal axons. These deposits were positive for several lysosomal proteins and other marker proteins typical for neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disease. However, the lysosomal pH of Clcn6(-/-) neurons appeared normal. CLCN6 is a candidate gene for mild forms of human NCL. Analysis of 75 NCL patients identified ClC-6 amino acid exchanges in two patients but failed to prove a causative role of CLCN6 in that disease.