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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cells, Cultured
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Chloride Channels / deficiency*
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Chloride Channels / genetics
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Chloride Channels / metabolism
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Gene Expression
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Hippocampus / metabolism
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Hippocampus / pathology
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Humans
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Hydrogen-Ion Concentration
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Lysosomal Storage Diseases, Nervous System / etiology*
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Lysosomal Storage Diseases, Nervous System / genetics
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Lysosomal Storage Diseases, Nervous System / metabolism
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Lysosomal Storage Diseases, Nervous System / pathology
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Lysosomes / metabolism
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Lysosomes / pathology
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Mice
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Mice, Knockout
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Mice, Mutant Strains
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Mice, Transgenic
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Mitochondrial Proton-Translocating ATPases / metabolism
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Nerve Degeneration / etiology*
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Nerve Degeneration / genetics
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Nerve Degeneration / metabolism
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Nerve Degeneration / pathology
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Neuronal Ceroid-Lipofuscinoses / etiology
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Neuronal Ceroid-Lipofuscinoses / genetics
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Neuronal Ceroid-Lipofuscinoses / metabolism
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Neuronal Ceroid-Lipofuscinoses / pathology
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Neurons / metabolism
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Neurons / pathology
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Osteopetrosis / genetics
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Osteopetrosis / metabolism
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Osteopetrosis / pathology
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Phenotype
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Retinal Degeneration / genetics
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Retinal Degeneration / metabolism
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Retinal Degeneration / pathology
Substances
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Chloride Channels
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Clcn7 protein, mouse
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mitochondrial ATPase subunit c
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Mitochondrial Proton-Translocating ATPases