title: CLC-3 deficiency leads to phenotypes similar to human neuronal ceroid lipofuscinosis.
abstract: BACKGROUND
  CLC-3 is a member of the CLC chloride channel family and is widely expressed in mammalian tissues. To determine the physiological role of CLC-3, we generated CLC-3-deficient mice (Clcn3-/- ) by targeted gene disruption.
  
  
  RESULTS
  Together with developmental retardation and higher mortality, the Clcn3-/- mice showed neurological manifestations such as blindness, motor coordination deficit, and spontaneous hyperlocomotion. In histological analysis, the Clcn3-/- mice showed a pattern of progressive degeneration of the retina, hippocampus and ileal mucosa, which resembled the phenotype observed in cathepsin D knockout mice. The defect of cathepsin D results in a lysosomal accumulation of ceroid lipofuscin containing the mitochondrial F1F0 ATPase subunit c. In immunohistochemistry and Western blot analysis, we found that the subunit c was heavily accumulated in the lysosome of Clcn3-/- mice. Furthermore, we detected an elevation in the endosomal pH of the Clcn3-/- mice.
  
  
  CONCLUSIONS
  These results indicated that the neurodegeneration observed in the Clcn3-/- mice was caused by an abnormality in the machinery which degrades the cellular protein and was associated with the phenotype of neuronal ceroid lipofuscinosis (NCL). The elevated endosomal pH could be an important factor in the pathogenesis of NCL.
authors.affiliation: Homeostasis Medicine and Nephrology, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima Bunkyo Tokyo 113-8519, Japan.
authors.forename: Momono
authors.initials: M
authors.lastname: Yoshikawa
authors.forename: Shinichi
authors.initials: S
authors.lastname: Uchida
authors.forename: Junji
authors.initials: J
authors.lastname: Ezaki
authors.forename: Tatemitsu
authors.initials: T
authors.lastname: Rai
authors.forename: Atsushi
authors.initials: A
authors.lastname: Hayama
authors.forename: Katsuki
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Yujiro
authors.initials: Y
authors.lastname: Kida
authors.forename: Masaki
authors.initials: M
authors.lastname: Noda
authors.forename: Masato
authors.initials: M
authors.lastname: Koike
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Uchiyama
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Marumo
authors.forename: Eiki
authors.initials: E
authors.lastname: Kominami
authors.forename: Sei
authors.initials: S
authors.lastname: Sasaki
mesh_terms: D000818:Animals; D002402:Cathepsin D / Q000172:deficiency; D018118:Chloride Channels / Q000172:deficiency / Q000502:physiology*; D004195:Disease Models, Animal; D011992:Endosomes / Q000378:metabolism; D006624:Hippocampus / Q000648:ultrastructure; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009457:Neuroglia / Q000648:ultrastructure; D009472:Neuronal Ceroid-Lipofuscinoses / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology; D009474:Neurons / Q000648:ultrastructure; D010641:Phenotype; D006180:Proton-Translocating ATPases / Q000378:metabolism
chemical_list: D018118:Chloride Channels; C115376:ClC-3 channel; D002402:Cathepsin D; D006180:Proton-Translocating ATPases