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

  • Mallorie Poët
  • Uwe Kornak
  • Michaela Schweizer
  • Anselm A Zdebik
  • Olaf Scheel
  • Sabine Hoelter
  • Wolfgang Wurst
  • Anja Schmitt
  • Jens C Fuhrmann
  • Rosa Planells-Cases
  • Sara E Mole
  • Christian Hübner
  • Thomas J Jentsch

Beteiligte Einrichtungen

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.

Bibliografische Daten

OriginalspracheDeutsch
Aufsatznummer37
ISSN0027-8424
StatusVeröffentlicht - 2006
pubmed 16950870