Transport and distribution of 3-hydroxyglutaric acid before and during induced encephalopathic crises in a mouse model of glutaric aciduria type 1.
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.
Keyser
Britta
B
Children's Hospital, Department of Biochemistry, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.
Glatzel
Markus
M
Stellmer
Franziska
F
Kortmann
Bastian
B
Lukacs
Zoltan
Z
Kölker
Stefan
S
Sauer
Sven W
SW
Muschol
Nicole
N
Herdering
Wilhelm
W
Thiem
Joachim
J
Goodman
Stephen I
SI
Koeller
David M
DM
Ullrich
Kurt
K
Braulke
Thomas
T
Mühlhausen
Chris
C
D000592:Amino Acid Metabolism, Inborn Errors / Q000150:complications / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D001921:Brain / Q000378:metabolism / Q000473:pathology; D001927:Brain Diseases / Q000209:etiology / Q000378:metabolism*; D003911:Dextrans / Q000378:metabolism; D004195:Disease Models, Animal; D005977:Glutarates / Q000378:metabolism*; D050770:Glutaryl-CoA Dehydrogenase / Q000172:deficiency* / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
C108959:3-hydroxyglutaric acid; D003911:Dextrans; D005977:Glutarates; D050770:Glutaryl-CoA Dehydrogenase