Intracerebral accumulation of glutaric and 3-hydroxyglutaric acids secondary to limited flux across the blood-brain barrier constitute a biochemical risk factor for neurodegeneration in glutaryl-CoA dehydrogenase deficiency.
Glutaric acid (GA) and 3-hydroxyglutaric acids (3-OH-GA) are key metabolites in glutaryl co-enzyme A dehydrogenase (GCDH) deficiency and are both considered to be potential neurotoxins. As cerebral concentrations of GA and 3-OH-GA have not yet been studied systematically, we investigated the tissue-specific distribution of these organic acids and glutarylcarnitine in brain, liver, skeletal and heart muscle of Gcdh-deficient mice as well as in hepatic Gcdh-/- mice and in C57Bl/6 mice following intraperitoneal loading. Furthermore, we determined the flux of GA and 3-OH-GA across the blood-brain barrier (BBB) using porcine brain microvessel endothelial cells. Concentrations of GA, 3-OH-GA and glutarylcarnitine were significantly elevated in all tissues of Gcdh-/- mice. Strikingly, cerebral concentrations of GA and 3-OH-GA were unexpectedly high, reaching similar concentrations as those found in liver. In contrast, cerebral concentrations of these organic acids remained low in hepatic Gcdh-/- mice and after intraperitoneal injection of GA and 3-OH-GA. These results suggest limited flux of GA and 3-OH-GA across the BBB, which was supported in cultured porcine brain capillary endothelial cells. In conclusion, we propose that an intracerebral de novo synthesis and subsequent trapping of GA and 3-OH-GA should be considered as a biochemical risk factor for neurodegeneration in GCDH deficiency.
Department of General Pediatrics, Division of Inborn Metabolic Diseases, University Children's Hospital Heidelberg, Heidelberg, Germany.
Sven W
SW
Sauer
Jürgen G
JG
Okun
Gert
G
Fricker
Anne
A
Mahringer
Ines
I
Müller
Linda R
LR
Crnic
Chris
C
Mühlhausen
Georg F
GF
Hoffmann
Friederike
F
Hörster
Stephen I
SI
Goodman
Cary O
CO
Harding
David M
DM
Koeller
Stefan
S
Kölker
D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D001692:Biological Transport / Q000502:physiology; D001812:Blood-Brain Barrier / Q000503:physiopathology*; D015153:Blotting, Western / Q000379:methods; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D002331:Carnitine / Q000031:analogs & derivatives / Q000378:metabolism; D002478:Cells, Cultured; D003998:Dicarboxylic Acids / Q000378:metabolism; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D005977:Glutarates / Q000378:metabolism*; D050770:Glutaryl-CoA Dehydrogenase / Q000172:deficiency*; D006321:Heart / Q000502:physiology; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D009132:Muscles / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000503:physiopathology*; D012307:Risk Factors; D018709:Statistics, Nonparametric; D013552:Swine; D013997:Time Factors; D014018:Tissue Distribution / Q000502:physiology
C108959:3-hydroxyglutaric acid; D000596:Amino Acids; D003998:Dicarboxylic Acids; D005977:Glutarates; C116917:acylcarnitine; D050770:Glutaryl-CoA Dehydrogenase; C035736:glutaric acid; D005947:Glucose; D002331:Carnitine