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 language | English (US) |
|---|---|
| Pages (from-to) | 385-390 |
| Number of pages | 6 |
| Journal | Biochimica et Biophysica Acta - Molecular Basis of Disease |
| Volume | 1782 |
| Issue number | 6 |
| DOIs | |
| State | Published - Jun 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 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 journal › Article
}
TY - JOUR
T1 - Transport and distribution of 3-hydroxyglutaric acid before and during induced encephalopathic crises in a mouse model of glutaric aciduria type 1
AU - Keyser, Britta
AU - Glatzel, Markus
AU - Stellmer, Franziska
AU - Kortmann, Bastian
AU - Lukacs, Zoltan
AU - Kölker, Stefan
AU - Sauer, Sven W.
AU - Muschol, Nicole
AU - Herdering, Wilhelm
AU - Thiem, Joachim
AU - Goodman, Stephen I.
AU - Koeller, David
AU - Ullrich, Kurt
AU - Braulke, Thomas
AU - Mühlhausen, Chris
PY - 2008/6
Y1 - 2008/6
N2 - 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.
AB - 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.
KW - Glutaric aciduria type 1
KW - Glutaryl-CoA dehydrogenase deficiency
KW - Metabolic crisis
KW - Metabolite distribution
KW - Mouse model
KW - Radiolabeled metabolite
UR - http://www.scopus.com/inward/record.url?scp=43549096394&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=43549096394&partnerID=8YFLogxK
U2 - 10.1016/j.bbadis.2008.02.008
DO - 10.1016/j.bbadis.2008.02.008
M3 - Article
C2 - 18348873
AN - SCOPUS:43549096394
VL - 1782
SP - 385
EP - 390
JO - Biochimica et Biophysica Acta - Molecular Basis of Disease
JF - Biochimica et Biophysica Acta - Molecular Basis of Disease
SN - 0925-4439
IS - 6
ER -