Loss of the chloride channel ClC-7 leads to lysosomal storage disease and neurodegeneration.
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.
Kasper
Dagmar
D
Zentrum für Molekulare Neurobiologie,Universität Hamburg, Hamburg, Germany.
Planells-Cases
Rosa
R
Fuhrmann
Jens C
JC
Scheel
Olaf
O
Zeitz
Oliver
O
Ruether
Klaus
K
Schmitt
Anja
A
Poët
Mallorie
M
Steinfeld
Robert
R
Schweizer
Michaela
M
Kornak
Uwe
U
Jentsch
Thomas J
TJ
D000818:Animals; D002478:Cells, Cultured; D018118:Chloride Channels / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D020140:Lysosomal Storage Diseases, Nervous System / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008247:Lysosomes / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D025261:Mitochondrial Proton-Translocating ATPases / Q000378:metabolism; D009410:Nerve Degeneration / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009472:Neuronal Ceroid-Lipofuscinoses / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010022:Osteopetrosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D012162:Retinal Degeneration / Q000235:genetics / Q000378:metabolism / Q000473:pathology
D018118:Chloride Channels; C490803:Clcn7 protein, mouse; C103607:mitochondrial ATPase subunit c; D025261:Mitochondrial Proton-Translocating ATPases