Transport and distribution of 3-hydroxyglutaric acid before and during induced encephalopathic crises in a mouse model of glutaric aciduria type 1

Britta Keyser, Markus Glatzel, Franziska Stellmer, Bastian Kortmann, Zoltan Lukacs, Stefan Kölker, Sven W. Sauer, Nicole Muschol, Wilhelm Herdering, Joachim Thiem, Stephen I. Goodman, David M. Koeller, Kurt Ullrich, Thomas Braulke, Chris Mühlhausen

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Abstract

Glutaric aciduria type 1 (GA1) is caused by the deficiency of glutaryl-CoA dehydrogenase (GCDH). Affected patients are prone to the development of encephalopathic crises during an early time window with destruction of striatal neurons and a subsequent irreversible movement disorder. 3-Hydroxyglutaric acid (3OHGA) accumulates in tissues and body fluids of GA1 patients and has been shown to mediate toxic effects on neuronal as well as endothelial cells. Injection of (3H)-labeled into 6 week-old Gcdh-/- mice, a model of GA1, revealed a low recovery in kidney, liver, or brain tissue that did not differ from control mice. Significant amounts of 3OHGA were found to be excreted via the intestinal tract. Exposure of Gcdh-/- mice to a high protein diet led to an encephalopathic crisis, vacuolization in the brain, and death after 4-5 days. Under these conditions, high amounts of injected 3H-3OHGA were found in kidneys of Gcdh-/- mice, whereas the radioactivity recovered in brain and blood was reduced. The data demonstrate that under conditions mimicking encephalopathic crises the blood-brain barrier appears to remain intact.

Original languageEnglish (US)
Pages (from-to)385-390
Number of pages6
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1782
Issue number6
DOIs
StatePublished - Jun 1 2008

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Keywords

  • Glutaric aciduria type 1
  • Glutaryl-CoA dehydrogenase deficiency
  • Metabolic crisis
  • Metabolite distribution
  • Mouse model
  • Radiolabeled metabolite

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology

Cite this

Keyser, B., Glatzel, M., Stellmer, F., Kortmann, B., Lukacs, Z., Kölker, S., Sauer, S. W., Muschol, N., Herdering, W., Thiem, J., Goodman, S. I., Koeller, D. M., Ullrich, K., Braulke, T., & Mühlhausen, C. (2008). Transport and distribution of 3-hydroxyglutaric acid before and during induced encephalopathic crises in a mouse model of glutaric aciduria type 1. Biochimica et Biophysica Acta - Molecular Basis of Disease, 1782(6), 385-390. https://doi.org/10.1016/j.bbadis.2008.02.008