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

Author:

Morland Cecilie123,Frøland Anne-Sofie145,Pettersen Mi Nguyen1,Storm-Mathisen Jon2,Gundersen Vidar26,Rise Frode5,Hassel Bjørnar14

Affiliation:

1. Norwegian Defense Research Establishment, Kjeller, Norway

2. Department of Anatomy and Centre for Molecular Biology and Neuroscience, University of Oslo, Oslo, Norway

3. Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Oslo, Norway

4. Department of Complex Neurology and Neurohabilitation, Oslo University Hospital and University of Oslo, Oslo, Norway

5. Department of Chemistry, University of Oslo, Oslo, Norway

6. Department of Neurology, Oslo University Hospital, Oslo, Norway

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.

Publisher

Portland Press Ltd.

Subject

Cell Biology,Molecular Biology,Biochemistry

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