title: Focal neurometabolic alterations in mice deficient for succinate semialdehyde dehydrogenase.
abstract: Metabolite profiling in succinate semialdehyde dehydrogenase (SSADH; Aldh5a1-/-) deficient mice previously revealed elevated gamma-hydroxybutyrate (GHB) and total GABA in urine and total brain and liver extracts. In this study, we extend our metabolic characterization of these mutant mice by documenting elevated GHB and total GABA in homogenates of mutant kidney, pancreas and heart. We quantified beta-alanine (a GABA homolog and putative neurotransmitter) to address its potential role in pathophysiology. We found normal levels of beta-alanine in urine and total homogenates of mutant brain, heart and pancreas, but elevated concentrations in mutant kidney and liver extracts. Amino acid analysis in mutant total brain homogenates revealed no abnormalities except for significantly decreased glutamine, which was normal in mutant liver and kidney extracts. Regional amino acid analysis (frontal cortex, parietal cortex, hippocampus and cerebellum) in mutant mice confirmed glutamine results. Glutamine synthetase protein and mRNA levels in homogenates of mutant mouse brain were normal. We profiled organic acid patterns in mutant brain homogenates to assess brain oxidative metabolism and found normal concentrations of Kreb's cycle intermediates but increased 4,5-dihydroxyhexanoic acid (a postulated derivative of succinic semialdehyde) levels. We conclude that SSADH-deficient mice represent a valid metabolic model of human SSADH deficiency, manifesting focal neurometabolic abnormalities which could provide key insights into pathophysiologic mechanisms.
authors.affiliation: Department of Molecular and Medical Genetics and Pediatrics, Oregon Health & Science University, Portland 97201, USA. gibsonm@ohsu.edu
authors.forename: K M
authors.initials: KM
authors.lastname: Gibson
authors.forename: D S M
authors.initials: DS
authors.lastname: Schor
authors.forename: M
authors.initials: M
authors.lastname: Gupta
authors.forename: W S
authors.initials: WS
authors.lastname: Guerand
authors.forename: H
authors.initials: H
authors.lastname: Senephansiri
authors.forename: T G
authors.initials: TG
authors.lastname: Burlingame
authors.forename: H
authors.initials: H
authors.lastname: Bartels
authors.forename: B M
authors.initials: BM
authors.lastname: Hogema
authors.forename: T
authors.initials: T
authors.lastname: Bottiglieri
authors.forename: W
authors.initials: W
authors.lastname: Froestl
authors.forename: O C
authors.initials: OC
authors.lastname: Snead
authors.forename: M
authors.initials: M
authors.lastname: Grompe
authors.forename: C
authors.initials: C
authors.lastname: Jakobs
mesh_terms: D000445:Aldehyde Oxidoreductases / Q000172:deficiency*; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism*; D002264:Carboxylic Acids / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005974:Glutamate-Ammonia Ligase / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism; D009928:Organ Specificity; D010084:Oxidation-Reduction; D010179:Pancreas / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012978:Sodium Oxybate / Q000378:metabolism; D050644:Succinate-Semialdehyde Dehydrogenase; D015091:beta-Alanine / Q000378:metabolism / Q000652:urine; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D002264:Carboxylic Acids; D012333:RNA, Messenger; D005973:Glutamine; D015091:beta-Alanine; D005680:gamma-Aminobutyric Acid; D012978:Sodium Oxybate; D000445:Aldehyde Oxidoreductases; D050644:Succinate-Semialdehyde Dehydrogenase; D005974:Glutamate-Ammonia Ligase