On the neurotoxicity of glutaric, 3-hydroxyglutaric, and trans-glutaconic acids in glutaric acidemia type 1

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

SN - 0360-4012

VL - 77

SP - 143

EP - 147

JO - Journal of Neuroscience Research

JF - Journal of Neuroscience Research

IS - 1

ER -