On the neurotoxicity of glutaric, 3-hydroxyglutaric, and trans-glutaconic acids in glutaric acidemia type 1
Research output: Contribution to journal › Journal article › Research › peer-review
Standard
On the neurotoxicity of glutaric, 3-hydroxyglutaric, and trans-glutaconic acids in glutaric acidemia type 1. / Lund, Trine Meldgaard; Christensen, E; Kristensen, A S; Schousboe, A; Lund, A M.
In: Journal of Neuroscience Research, Vol. 77, No. 1, 2004, p. 143-7.Research output: Contribution to journal › Journal article › Research › peer-review
Harvard
APA
Vancouver
Author
Bibtex
}
RIS
TY - JOUR
T1 - On the neurotoxicity of glutaric, 3-hydroxyglutaric, and trans-glutaconic acids in glutaric acidemia type 1
AU - Lund, Trine Meldgaard
AU - Christensen, E
AU - Kristensen, A S
AU - Schousboe, A
AU - Lund, A M
N1 - Copyright 2004 Wiley-Liss, Inc.
PY - 2004
Y1 - 2004
N2 - Glutaric acidemia type 1 (GA1) is an autosomal recessively inherited deficiency of glutaryl-CoA dehydrogenase. Accumulating metabolites, 3-hydroxyglutaric (3-OH-GA), glutaric (GA), and trans-glutaconic (TG) acids, have been proposed to be involved in the development of the striatal degeneration seen in children with GA1 via an excitotoxic mechanism. We have studied the extent to which 3-OH-GA, GA, and TG are neurotoxic and whether neurotoxicity is caused by an excitotoxic mechanism in which 3-OH-GA, GA, or TG overactivates N-methyl-D-aspartate (NMDA) receptors. In cultured mouse neocortical neurons, all three compounds were weakly neurotoxic, possibly through activation of NMDA receptors. However, further studies in the rat cortical wedge preparation and with NMDA receptors expressed in Xenopus oocytes could not confirm an interaction of the compounds with NMDA receptors. It is concluded that the metabolites 3-OH-GA, GA, and TG are only weak neurotoxins and that the neurodegenerative cascade destroying the striatum in patients with GA1 involves mainly mechanisms other than excitoxicity.
AB - Glutaric acidemia type 1 (GA1) is an autosomal recessively inherited deficiency of glutaryl-CoA dehydrogenase. Accumulating metabolites, 3-hydroxyglutaric (3-OH-GA), glutaric (GA), and trans-glutaconic (TG) acids, have been proposed to be involved in the development of the striatal degeneration seen in children with GA1 via an excitotoxic mechanism. We have studied the extent to which 3-OH-GA, GA, and TG are neurotoxic and whether neurotoxicity is caused by an excitotoxic mechanism in which 3-OH-GA, GA, or TG overactivates N-methyl-D-aspartate (NMDA) receptors. In cultured mouse neocortical neurons, all three compounds were weakly neurotoxic, possibly through activation of NMDA receptors. However, further studies in the rat cortical wedge preparation and with NMDA receptors expressed in Xenopus oocytes could not confirm an interaction of the compounds with NMDA receptors. It is concluded that the metabolites 3-OH-GA, GA, and TG are only weak neurotoxins and that the neurodegenerative cascade destroying the striatum in patients with GA1 involves mainly mechanisms other than excitoxicity.
KW - Animals
KW - Brain Diseases, Metabolic, Inborn
KW - Cell Death
KW - Cells, Cultured
KW - Cerebral Cortex
KW - Corpus Striatum
KW - Fetus
KW - Glutarates
KW - Glutaryl-CoA Dehydrogenase
KW - Membrane Potentials
KW - Mice
KW - Nerve Degeneration
KW - Neurons
KW - Neurotoxins
KW - Oocytes
KW - Oxidoreductases Acting on CH-CH Group Donors
KW - Rats
KW - Receptors, N-Methyl-D-Aspartate
KW - Xenopus
U2 - 10.1002/jnr.20136
DO - 10.1002/jnr.20136
M3 - Journal article
C2 - 15197747
VL - 77
SP - 143
EP - 147
JO - Journal of Neuroscience Research
JF - Journal of Neuroscience Research
SN - 0360-4012
IS - 1
ER -
ID: 36057737