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Lysosomal storage disease upon disruption of the neuronal chloride transport protein ClC-6.


ABSTRACT: 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.

SUBMITTER: Poet M 

PROVIDER: S-EPMC1564226 | biostudies-literature | 2006 Sep

REPOSITORIES: biostudies-literature

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Lysosomal storage disease upon disruption of the neuronal chloride transport protein ClC-6.

Poët Mallorie M   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  

Proceedings of the National Academy of Sciences of the United States of America 20060901 37


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  ...[more]

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