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

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.

• Authors: Dagmar Kasper, Rosa Planells-Cases, Jens C Fuhrmann, Olaf Scheel, Oliver Zeitz, Klaus Ruether, Anja Schmitt, Mallorie Poët, Robert Steinfeld, Michaela Schweizer, Uwe Kornak, Thomas J Jentsch
• Journal: The EMBO journal (EMBO J) Vol. 24 Issue 5 Pg. 1079-91 (Mar 09 2005) ISSN: 0261-4189 [Print] England
• PMID: 15706348 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Chloride Channels
• Clcn7 protein, mouse
• mitochondrial ATPase subunit c
• Mitochondrial Proton-Translocating ATPases

Topics

• Animals
• Cells, Cultured
• Chloride Channels (deficiency, genetics, metabolism)
• Gene Expression
• Hippocampus (metabolism, pathology)
• Humans
• Hydrogen-Ion Concentration
• Lysosomal Storage Diseases, Nervous System (etiology, genetics, metabolism, pathology)
• Lysosomes (metabolism, pathology)
• Mice
• Mice, Knockout
• Mice, Mutant Strains
• Mice, Transgenic
• Mitochondrial Proton-Translocating ATPases (metabolism)
• Nerve Degeneration (etiology, genetics, metabolism, pathology)
• Neuronal Ceroid-Lipofuscinoses (etiology, genetics, metabolism, pathology)
• Neurons (metabolism, pathology)
• Osteopetrosis (genetics, metabolism, pathology)
• Phenotype
• Retinal Degeneration (genetics, metabolism, pathology)