Loss of the chloride channel ClC-7 leads to lysosomal storage disease and neurodegeneration
2005 | journal article. A publication with affiliation to the University of Göttingen.
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Loss of the chloride channel ClC-7 leads to lysosomal storage disease and neurodegeneration
Kasper, D.; Planells-Cases, R.; Fuhrmann, J. C.; Scheel, O.; Zeitz, O.; Ruether, K. & Schmitt, A. et al. (2005)
The EMBO Journal, 24(5) pp. 1079-1091. DOI: https://doi.org/10.1038/sj.emboj.7600576
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- Authors
- Kasper, D.; Planells-Cases, R.; Fuhrmann, J. C.; Scheel, O.; Zeitz, Oliver; Ruether, K.; Schmitt, A.; Poet, M.; Steinfeld, Robert ; Schweizer, M.; Kornak, U. ; Jentsch, Thomas 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.
- Issue Date
- 2005
- Status
- published
- Journal
- The EMBO Journal
- ISSN
- 0261-4189