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

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• 作者：Britta Keyser ; Markus Glatzel ; Franziska Stellmer ; Bastian Kortmann ; Zoltan Lukacs ; Stefan K&#xf6 ; lker ; Sven W. Sauer ; Nicole Muschol ; Wilhelm Herdering ; Joachim Thiem ; Stephen I. Goodman ; David M. Ko
• 关键词：Radiolabeled metabolite ; Glutaric aciduria type 1 ; Mouse model ; Metabolite distribution ; Glutaryl-CoA dehydrogenase deficiency ; Metabolic crisis
• 刊名：Biochimica et Biophysica Acta (BBA)/Molecular Basis of Disease
• 出版年：2008
• 期刊代码：19_09254439
• 类别：bio
• 出版时间：June 2008
• 卷：1782
• 期：6
• 页码：385-390
• 文件大小：693 K

摘要

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.