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.