Children with the inborn metabolic disease propionic acidemia suffer from lethargy and striatal degeneration with ensuing motor impairment. The present study focusses on the underlying neurotoxic mechanisms, and the selective vulnerability of striatal (GABAergic) neurons.
Propionate was shown to dose-dependently Inhibit GABA transaminase, a key enzyme of the GABA shunt, and thereby for the overall glucose metabolism in GABergic neurons. Inhibited glucose metabolism may explain why GABAergic neurons die in response to propionate. The study also identify increased GABA levels in the brain, and increased release of GABA from isolated nerve terminals. Increased GABA transmission may explain the lethargy seen in these patients.
Propionate enters GABAergic neurons, inhibits GABA transaminase, causes GABA accumulation and lethargy in a model of propionic acidemia.
Cecilie Morland, Anne-Sofie Frøland, Mi Nyguyen Pettersen, Jon Storm-Mathisen, Vidar Gundersen, Frode Rise, Bjørnar Hassel
Biochemical Journal Jan 16, 2018, BCJ20170814; DOI: https://doi.org/10.1042/BCJ20170814
Read the article here.