Focal neurometabolic alterations in mice deficient for succinate semialdehyde dehydrogenase

K. M. Gibson, D. S M Schor, M. Gupta, W. S. Guerand, H. Senephansiri, T. G. Burlingame, H. Bartels, B. M. Hogema, T. Bottiglieri, W. Froestl, O. C. Snead, Markus Grompe, C. Jakobs

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Abstract

Metabolite profiling in succinate semialdehyde dehydrogenase (SSADH; Aldh5a1-/-) deficient mice previously revealed elevated γ-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 β-alanine (a GABA homolog and putative neurotransmitter) to address its potential role in pathophysiology. We found normal levels of β-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.

Original languageEnglish (US)
Pages (from-to)71-79
Number of pages9
JournalJournal of Neurochemistry
Volume81
Issue number1
DOIs
StatePublished - 2002

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Succinate-Semialdehyde Dehydrogenase
Brain
Liver Extracts
gamma-Aminobutyric Acid
Glutamine
Kidney
Alanine
Pancreas
Urine
Hydroxybutyrates
Amino Acids
Glutamate-Ammonia Ligase
Parietal Lobe
Acids
Organic acids
Frontal Lobe
Metabolites
Metabolism
Liver
Cerebellum

Keywords

  • β-alanine
  • γ-hydroxybutyrate
  • 4,5-dihydroxyhexanoic acid
  • GABA
  • Glutamine
  • Succinate semialdehyde dehydrogenase

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Gibson, K. M., Schor, D. S. M., Gupta, M., Guerand, W. S., Senephansiri, H., Burlingame, T. G., ... Jakobs, C. (2002). Focal neurometabolic alterations in mice deficient for succinate semialdehyde dehydrogenase. Journal of Neurochemistry, 81(1), 71-79. https://doi.org/10.1046/j.1471-4159.2002.00784.x

Focal neurometabolic alterations in mice deficient for succinate semialdehyde dehydrogenase. / Gibson, K. M.; Schor, D. S M; Gupta, M.; Guerand, W. S.; Senephansiri, H.; Burlingame, T. G.; Bartels, H.; Hogema, B. M.; Bottiglieri, T.; Froestl, W.; Snead, O. C.; Grompe, Markus; Jakobs, C.

In: Journal of Neurochemistry, Vol. 81, No. 1, 2002, p. 71-79.

Research output: Contribution to journalArticle

Gibson, KM, Schor, DSM, Gupta, M, Guerand, WS, Senephansiri, H, Burlingame, TG, Bartels, H, Hogema, BM, Bottiglieri, T, Froestl, W, Snead, OC, Grompe, M & Jakobs, C 2002, 'Focal neurometabolic alterations in mice deficient for succinate semialdehyde dehydrogenase', Journal of Neurochemistry, vol. 81, no. 1, pp. 71-79. https://doi.org/10.1046/j.1471-4159.2002.00784.x
Gibson, K. M. ; Schor, D. S M ; Gupta, M. ; Guerand, W. S. ; Senephansiri, H. ; Burlingame, T. G. ; Bartels, H. ; Hogema, B. M. ; Bottiglieri, T. ; Froestl, W. ; Snead, O. C. ; Grompe, Markus ; Jakobs, C. / Focal neurometabolic alterations in mice deficient for succinate semialdehyde dehydrogenase. In: Journal of Neurochemistry. 2002 ; Vol. 81, No. 1. pp. 71-79.
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AU - Senephansiri, H.

AU - Burlingame, T. G.

AU - Bartels, H.

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