Lysosomal storage disease upon disruption of the neuronal chloride transport protein ClC-6.
Mammalian CLC proteins function as Cl(-) channels or as electrogenic Cl(-)/H(+) exchangers and are present in the plasma membrane and intracellular vesicles. We now show that the ClC-6 protein is almost exclusively expressed in neurons of the central and peripheral nervous systems, with a particularly high expression in dorsal root ganglia. ClC-6 colocalized with markers for late endosomes in neuronal cell bodies. The disruption of ClC-6 in mice reduced their pain sensitivity and caused moderate behavioral abnormalities. Neuronal tissues showed autofluorescence at initial axon segments. At these sites, electron microscopy revealed electron-dense storage material that caused a pathological enlargement of proximal axons. These deposits were positive for several lysosomal proteins and other marker proteins typical for neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disease. However, the lysosomal pH of Clcn6(-/-) neurons appeared normal. CLCN6 is a candidate gene for mild forms of human NCL. Analysis of 75 NCL patients identified ClC-6 amino acid exchanges in two patients but failed to prove a causative role of CLCN6 in that disease.
Poët
Mallorie
M
Zentrum für Molekulare Neurobiologie, Universität Hamburg, Falkenried 94, D-20246 Hamburg, Germany.
Kornak
Uwe
U
Schweizer
Michaela
M
Zdebik
Anselm A
AA
Scheel
Olaf
O
Hoelter
Sabine
S
Wurst
Wolfgang
W
Schmitt
Anja
A
Fuhrmann
Jens C
JC
Planells-Cases
Rosa
R
Mole
Sara E
SE
Hübner
Christian A
CA
Jentsch
Thomas J
TJ
D000818:Animals; D001369:Axons / Q000378:metabolism / Q000648:ultrastructure; D001522:Behavior, Animal; D015415:Biomarkers / Q000032:analysis; D018118:Chloride Channels / Q000032:analysis / Q000235:genetics* / Q000502:physiology*; D004252:DNA Mutational Analysis; D011992:Endosomes / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D020869:Gene Expression Profiling; D006624:Hippocampus / Q000503:physiopathology / Q000648:ultrastructure*; D006801:Humans; D016464:Lysosomal Storage Diseases / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D008247:Lysosomes / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D051379:Mice; D018345:Mice, Knockout; D009472:Neuronal Ceroid-Lipofuscinoses / Q000235:genetics; D009474:Neurons / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D010146:Pain / Q000235:genetics / Q000503:physiopathology
D015415:Biomarkers; D018118:Chloride Channels; C490800:Clcn6 protein, mouse