title: High resolution 1H NMR-based metabolomics indicates a neurotransmitter cycling deficit in cerebral tissue from a mouse model of Batten disease.
abstract: The neuronal ceroid lipofuscinoses (NCLs) constitute a range of progressive neurological disorders primarily affecting children. Although six of the causative genes have been characterized, the underlying disease pathogenesis for this family of disorders is unknown. Using a metabolomics approach based on high resolution 1H NMR spectroscopy of the cortex, cerebellum, and remaining regions of the brain in conjunction with statistical pattern recognition, we report metabolic deficits associated with juvenile NCL in a Cln3 knock-out mouse model. Tissue from Cln3 null mutant mice aged 1-6 months was characterized by an increased glutamate concentration and a decrease in -amino butyric acid (GABA) concentration in aqueous extracts from the three regions of the brain. These changes are consistent with the reported altered expression of genes involved in glutamate metabolism in older mice and imply a change in neurotransmitter cycling between glutamate/glutamine and the production of GABA. Further variations in myo-inositol, creatine, and N-acetyl-aspartate were also identified. These metabolic changes were distinct from the normal aging/developmental process. Together, these changes represent the first documented pre-symptomatic symptoms of the Cln3 mouse at 1 month of age and demonstrate the versatility of 1H NMR spectroscopy as a tool for phenotyping mouse models of disease.
authors.affiliation: Department of Biochemistry, Tennis Court Road, University of Cambridge, Cambridge CB2 1GA, United Kingdom.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Pears
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Cooper
authors.forename: Hannah M
authors.initials: HM
authors.lastname: Mitchison
authors.forename: Russell J
authors.initials: RJ
authors.lastname: Mortishire-Smith
authors.forename: David A
authors.initials: DA
authors.lastname: Pearce
authors.forename: Julian L
authors.initials: JL
authors.lastname: Griffin
mesh_terms: D000375:Aging; D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D002531:Cerebellum / Q000473:pathology; D002540:Cerebral Cortex / Q000473:pathology; D003401:Creatine / Q000378:metabolism; D004195:Disease Models, Animal; D018698:Glutamic Acid / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism; D006801:Humans; D007294:Inositol / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D018832:Molecular Chaperones / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D009472:Neuronal Ceroid-Lipofuscinoses / Q000378:metabolism* / Q000473:pathology*; D018377:Neurotransmitter Agents / Q000378:metabolism*; D010641:Phenotype; D013053:Spectrophotometry; D013997:Time Factors; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: C102229:CLN3 protein, mouse; D008562:Membrane Glycoproteins; D018832:Molecular Chaperones; D018377:Neurotransmitter Agents; D005973:Glutamine; D001224:Aspartic Acid; D018698:Glutamic Acid; D007294:Inositol; D005680:gamma-Aminobutyric Acid; C000179:N-acetylaspartate; D003401:Creatine