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| 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 |
| ISSN: | 0261-4189 |
| Publisher: | Nature Publishing Group |
| Volume: | 24 |
| Number: | 5 |
| 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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