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Research article

Propionate enters GABAergic neurons, inhibits GABA transaminase, causes GABA accumulation and lethargy in a model of propionic acidemia

Cecilie Morland, Anne-Sofie Frøland, Mi Nguyen Pettersen, Jon Storm-Mathisen, Vidar Gundersen, Frode Rise, Bjørnar Hassel
Biochemical Journal Feb 16, 2018, 475 (4) 749-758; DOI: 10.1042/BCJ20170814
Cecilie Morland
Norwegian Defense Research Establishment, Kjeller, NorwayDepartment of Anatomy and Centre for Molecular Biology and Neuroscience, University of Oslo, Oslo, NorwayDepartment of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Oslo, Norway
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Anne-Sofie Frøland
Norwegian Defense Research Establishment, Kjeller, NorwayDepartment of Complex Neurology and Neurohabilitation, Oslo University Hospital and University of Oslo, Oslo, NorwayDepartment of Chemistry, University of Oslo, Oslo, Norway
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Mi Nguyen Pettersen
Norwegian Defense Research Establishment, Kjeller, Norway
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Jon Storm-Mathisen
Department of Anatomy and Centre for Molecular Biology and Neuroscience, University of Oslo, Oslo, Norway
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Vidar Gundersen
Department of Anatomy and Centre for Molecular Biology and Neuroscience, University of Oslo, Oslo, NorwayDepartment of Neurology, Oslo University Hospital, Oslo, Norway
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Frode Rise
Department of Chemistry, University of Oslo, Oslo, Norway
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Bjørnar Hassel
Norwegian Defense Research Establishment, Kjeller, NorwayDepartment of Complex Neurology and Neurohabilitation, Oslo University Hospital and University of Oslo, Oslo, Norway
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  • For correspondence: bjornar.hassel@ffi.no
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Abstract

Propionic acidemia is the accumulation of propionate in blood due to dysfunction of propionyl-CoA carboxylase. The condition causes lethargy and striatal degeneration with motor impairment in humans. How propionate exerts its toxic effect is unclear. Here, we show that intravenous administration of propionate causes dose-dependent propionate accumulation in the brain and transient lethargy in mice. Propionate, an inhibitor of histone deacetylase, entered GABAergic neurons, as could be seen from increased neuronal histone H4 acetylation in the striatum and neocortex. Propionate caused an increase in GABA (γ-amino butyric acid) levels in the brain, suggesting inhibition of GABA breakdown. In vitro propionate inhibited GABA transaminase with a Ki of ∼1 mmol/l. In isolated nerve endings, propionate caused increased release of GABA to the extracellular fluid. In vivo, propionate reduced cerebral glucose metabolism in both striatum and neocortex. We conclude that propionate-induced inhibition of GABA transaminase causes accumulation of GABA in the brain, leading to increased extracellular GABA concentration, which inhibits neuronal activity and causes lethargy. Propionate-mediated inhibition of neuronal GABA transaminase, an enzyme of the inner mitochondrial membrane, indicates entry of propionate into neuronal mitochondria. However, previous work has shown that neurons are unable to metabolize propionate oxidatively, leading us to conclude that propionyl-CoA synthetase is probably absent from neuronal mitochondria. Propionate-induced inhibition of energy metabolism in GABAergic neurons may render the striatum, in which >90% of the neurons are GABAergic, particularly vulnerable to degeneration in propionic acidemia.

  • autism
  • caudate
  • GABA transaminase
  • propionic acidemia
  • propionyl-CoA synthetase
  • striatum
  • Abbreviations

    GABA,
    γ-amino butyric acid;
    GFAP,
    glial fibrillary acidic protein;
    GSH,
    glutathione;
    i.v.,
    intravenous;
    NMRS,
    nuclear magnetic resonance spectroscopy;
    TCA cycle,
    tricarboxylic acid cycle
    • © 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society
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    February 2018

    Volume: 475 Issue: 4

    Biochemical Journal: 475 (4)
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    Propionate enters GABAergic neurons, inhibits GABA transaminase, causes GABA accumulation and lethargy in a model of propionic acidemia
    Cecilie Morland, Anne-Sofie Frøland, Mi Nguyen Pettersen, Jon Storm-Mathisen, Vidar Gundersen, Frode Rise, Bjørnar Hassel
    Biochemical Journal Feb 2018, 475 (4) 749-758; DOI: 10.1042/BCJ20170814
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    Propionate enters GABAergic neurons, inhibits GABA transaminase, causes GABA accumulation and lethargy in a model of propionic acidemia
    Cecilie Morland, Anne-Sofie Frøland, Mi Nguyen Pettersen, Jon Storm-Mathisen, Vidar Gundersen, Frode Rise, Bjørnar Hassel
    Biochemical Journal Feb 2018, 475 (4) 749-758; DOI: 10.1042/BCJ20170814

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    Keywords

    autism
    caudate
    GABA transaminase
    propionic acidemia
    propionyl-CoA synthetase
    striatum

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