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 Koeller, Kurt Ullrich, Thomas Braulke, Chris Mühlhausen

Research output: Contribution to journalArticle

22 Citations (Scopus)

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 2008

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Kidney
Corpus Striatum
Brain Death
Poisons
Movement Disorders
Brain
Body Fluids
Blood-Brain Barrier
Radioactivity
Endothelial Cells
Diet
Neurons
Injections
3-hydroxyglutaric acid
Glutaric Acidemia I
Liver
Proteins

Keywords

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

ASJC Scopus subject areas

  • Molecular Biology
  • Molecular Medicine
  • Biophysics

Cite this

Transport and distribution of 3-hydroxyglutaric acid before and during induced encephalopathic crises in a mouse model of glutaric aciduria type 1. / Keyser, Britta; Glatzel, Markus; Stellmer, Franziska; Kortmann, Bastian; Lukacs, Zoltan; Kölker, Stefan; Sauer, Sven W.; Muschol, Nicole; Herdering, Wilhelm; Thiem, Joachim; Goodman, Stephen I.; Koeller, David; Ullrich, Kurt; Braulke, Thomas; Mühlhausen, Chris.

In: Biochimica et Biophysica Acta - Molecular Basis of Disease, Vol. 1782, No. 6, 06.2008, p. 385-390.

Research output: Contribution to journalArticle

Keyser, B, Glatzel, M, Stellmer, F, Kortmann, B, Lukacs, Z, Kölker, S, Sauer, SW, Muschol, N, Herdering, W, Thiem, J, Goodman, SI, Koeller, D, 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, vol. 1782, no. 6, pp. 385-390. https://doi.org/10.1016/j.bbadis.2008.02.008
Keyser, Britta ; Glatzel, Markus ; Stellmer, Franziska ; Kortmann, Bastian ; Lukacs, Zoltan ; Kölker, Stefan ; Sauer, Sven W. ; Muschol, Nicole ; Herdering, Wilhelm ; Thiem, Joachim ; Goodman, Stephen I. ; Koeller, David ; Ullrich, Kurt ; Braulke, Thomas ; Mühlhausen, Chris. / Transport and distribution of 3-hydroxyglutaric acid before and during induced encephalopathic crises in a mouse model of glutaric aciduria type 1. In: Biochimica et Biophysica Acta - Molecular Basis of Disease. 2008 ; Vol. 1782, No. 6. pp. 385-390.
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