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Loss of the chloride channel ClC-7 leads to lysosomal storage disease and neurodegeneration

Item Type:Article
Title:Loss of the chloride channel ClC-7 leads to lysosomal storage disease and neurodegeneration
Creators Name:Kasper, D., Planells-Cases, R., Fuhrmann, J.C., Scheel, O., Zeitz, O., Ruether, K., Schmitt, A., Poet, M., Steinfeld, R., Schweizer, M., Kornak, U. and Jentsch, T.J.
Abstract:ClC-7 is a chloride channel of late endosomes and lysosomes. In osteoclasts, it may cooperate with H(+)-ATPases in acidifying the resorption lacuna. In mice and man, loss of ClC-7 or the H(+)-ATPase a3 subunit causes osteopetrosis, a disease characterized by defective bone resorption. We show that ClC-7 knockout mice additionally display neurodegeneration and severe lysosomal storage disease despite unchanged lysosomal pH in cultured neurons. Rescuing their bone phenotype by transgenic expression of ClC-7 in osteoclasts moderately increased their lifespan and revealed a further progression of the central nervous system pathology. Histological analysis demonstrated an accumulation of electron-dense material in neurons, autofluorescent structures, microglial activation and astrogliosis. Like in human neuronal ceroid lipofuscinosis, there was a strong accumulation of subunit c of the mitochondrial ATP synthase and increased amounts of lysosomal enzymes. Such alterations were minor or absent in ClC-3 knockout mice, despite a massive neurodegeneration. Osteopetrotic oc/oc mice, lacking a functional H(+)-ATPase a3 subunit, showed no comparable retinal or neuronal degeneration. There are important medical implications as defects in the H(+)-ATPase and ClC-7 can underlie human osteopetrosis.
Keywords:Channelopathy, NCL/TCIRG1, Transgenic Rescue, Animals, Mice
Source:EMBO Journal
Publisher:Nature Publishing Group
Page Range:1079-1091
Date:9 March 2005
Official Publication:https://doi.org/10.1038/sj.emboj.7600576
PubMed:View item in PubMed

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