title: Altered arginine metabolism in the central nervous system (CNS) of the Cln3-/- mouse model of juvenile Batten disease.
abstract: BACKGROUND
  Juvenile neuronal ceroid lipofuscinoses (JNCL) or juvenile Batten disease is a recessively inherited childhood neurodegenerative disorder resulting from a mutation in CLN3, which encodes a putative lysosomal protein of unknown function.
  
  
  OBJECTIVE
  Recent evidence suggests that a disruption in CLN3 function results in altered regulation of arginine transport into lysosomes, and may influence intracellular arginine levels. We sought to investigate the possible consequences of arginine dysregulation in the brain of the Cln3(-/-) mouse model of JNCL.
  
  
  METHODS
  Using a combination of enzyme assays, metabolite profiling, quantitative reverse-transcription polymerase chain reaction and Western blotting, we analysed the activities and expression of enzymes involved in arginine metabolism in the cerebral cortex and cerebellum of Cln3(-/-) mice over several developmental time points.
  
  
  RESULTS
  We report subtle, but significant changes in the activities of enzymes involved in the citrulline-NO recycling pathway, and altered regulation of neuronal nitric oxide synthase in the cortex and cerebellum of Cln3(-/-) mice. In addition, a significant decrease in arginine transport into cerebellar granule cells was observed, despite an apparent upregulation of the cationic amino acid transporter-1 transporter at the cell surface. Our results provide further evidence that CLN3 function and arginine homeostasis are intricately related, and that cellular mechanisms may act to compensate for the loss of this protein.
  
  
  CONCLUSIONS
  This and other studies indicate that CLN3 dysfunction in JNCL may result in multiple disturbances in metabolism that together contribute to the pathophysiological processes underlying this disease.
authors.affiliation: Center for Neural Development and Disease, University of Rochester School of Medicine and Dentistry, Rochester 14642, USA.
authors.forename: C-H
authors.initials: CH
authors.lastname: Chan
authors.forename: D
authors.initials: D
authors.lastname: Ramirez-Montealegre
authors.forename: D A
authors.initials: DA
authors.lastname: Pearce
mesh_terms: D000818:Animals; D001120:Arginine / Q000378:metabolism*; D001921:Brain / Q000254:growth & development / Q000378:metabolism*; D027201:Cationic Amino Acid Transporter 1 / Q000378:metabolism; D002478:Cells, Cultured; D002956:Citrulline / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D008099:Liver / Q000201:enzymology / Q000503:physiopathology; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D018832:Molecular Chaperones / Q000235:genetics*; D009472:Neuronal Ceroid-Lipofuscinoses / Q000378:metabolism*; D009474:Neurons / Q000502:physiology; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D020033:Protein Isoforms; D012333:RNA, Messenger / Q000378:metabolism; D014508:Urea / Q000378:metabolism
chemical_list: C102229:CLN3 protein, mouse; D027201:Cationic Amino Acid Transporter 1; D008562:Membrane Glycoproteins; D018832:Molecular Chaperones; D020033:Protein Isoforms; D012333:RNA, Messenger; D002956:Citrulline; D009569:Nitric Oxide; D014508:Urea; D001120:Arginine; D019001:Nitric Oxide Synthase