Glutaric Acid and Its Metabolites Cause Apoptosis in Immature Oligodendrocytes: A Novel Mechanism of White Matter Degeneration in Glutaryl-CoA Dehydrogenase Deficiency

Gerstner, Bettina; Gratopp, Alexander; Marcinkowski, Monika; Sifringer, Marco; Obladen, Michael; Bührer, Christoph

doi:10.1203/01.pdr.0000157727.21503.8d

Cited by 32 publications

(18 citation statements)

References 31 publications

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“…According to results obtained by Gerstner and colleagues, OLN-93 cells lack the expression of several subunits of NMDA receptor i.e. NR1, NR2A and NR2B, which may suggest no functional activity of NMDA receptors [22] and may explain no or marginal effect of several glutamate receptor antagonists and agonists on oligodendrocytes in our study. However, previous study characterizing KYNA synthesis in OLN-93 cells showed that KYNA production had been altered due to glutamate and AMPA treatment, suggesting their interaction with adequate receptors.…”

Section: Discussionsupporting

confidence: 59%

Kynurenic Acid Induces Impairment of Oligodendrocyte Viability: On the Role of Glutamatergic Mechanisms

et al. 2016

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Kynurenic acid (KYNA) is an end stage product of tryptophan metabolism with a variety of functions in the human body, both in the central nervous system (CNS) and in other organs. Although its activity in the human brain has been widely studied and effects on neural cells were emphasized, the effect of KYNA on oligodendroglial cells remains unknown. Present study aims at describing the activity of high concentration of KYNA in OLN-93 cells. The inhibition of OLN-93 oligodendrocytes viability by KYNA in a medium with reduced serum concentration has been demonstrated. Although decreased metabolic activity of KYNA treated OLN-93 cells was shown, the cells proliferation was not altered. KYNA treatment did not alter morphology as well as expression level of cell cycle and proliferation regulating proteins. Furthermore, glutamate receptor antagonists and agonists did not alter the inhibitory effect of KYNA on viability of OLN-93 oligodendrocytes. This study contributes to the elucidation of effects of KYNA on oligodendrocytes in vitro, yet further analyses are necessary to explain the mechanisms behind the damage and loss of myelin sheaths.

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Section: Discussionsupporting

confidence: 59%

Kynurenic Acid Induces Impairment of Oligodendrocyte Viability: On the Role of Glutamatergic Mechanisms

et al. 2016

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“…Because these compounds do not readily cross the blood-brain barrier, they accumulate within the brain (Kölker et al 2002a, b; Junqueira et al 2003, 2004; Porciuncula et al 2004; Wajner et al 2004; Gerstner et al 2005; Sauer et al 2006), where they may inhibit the delivery of neurometabolic precursors.…”

Section: Discussionmentioning

confidence: 99%

The sodium‐dependent di‐ and tricarboxylate transporter, NaCT, is not responsible for the uptake of D‐, L‐2‐hydroxyglutarate and 3‐hydroxyglutarate into neurons

Brauburger

Burckhardt

2011

J of Inher Metab Disea

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Concentrations of glutarate (GA) and its derivatives such as 3-hydroxyglutarate (3OHGA), D- (D-2OHGA) and L-2-hydroxyglutarate (L-2OHGA) are increased in plasma, cerebrospinal fluid (CSF) and urine of patients suffering from different forms of organic acidurias. It has been proposed that these derivatives cause neuronal damage in these patients, leading to dystonic and dyskinetic movement disorders. We have recently shown that these compounds are eliminated by the kidneys via the human organic anion transporters, OAT1 and OAT4, and the sodium-dependent dicarboxylate transporter 3, NaDC3. In neurons, where most of the damage occurs, a sodium-dependent citrate transporter, NaCT, has been identified. Therefore, we investigated the impact of GA derivatives on hNaCT by two-electrode voltage clamp and tracer uptake studies. None of these compounds induced substrate-associated currents in hNaCT-expressing Xenopus laevis oocytes nor did GA derivatives inhibit the uptake of citrate, the prototypical substrate of hNaCT. In contrast, D- and L-2OHGA, but not 3OHGA, showed affinities to NaDC3, indicating that D- and L-2OHGA impair the uptake of dicarboxylates into astrocytes thereby possibly interfering with their feeding of tricarboxylic acid cycle intermediates to neurons.

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“…Moreover, some in vitro studies failed to demonstrate significant neurotoxic effects of GA and 3-OH-GA (Freudenberg et al 2004;Lund et al 2004) or indicated toxic effects on cells lacking NMDA receptor expression (immature oligodendrocytes (Gerstner et al 2005); human, dermal, microvascular endothelial cells (Mü hlhausen et al 2006)). These findings suggest additional or alternative factors contributing to the pathogenesis of GDD.…”

Section: Excitatory Neurotransmission: Primary Excitotoxicity?mentioning

confidence: 99%

Biochemistry and bioenergetics of glutaryl‐CoA dehydrogenase deficiency

Sauer

2007

J of Inher Metab Disea

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Glutaryl-CoA dehydrogenase (GCDH) is a central enzyme in the catabolic pathway of L-tryptophan, L-lysine, and L-hydroxylysine which catalyses the oxidative decarboxylation of glutaryl-CoA to crotonyl-CoA and CO2. Glutaryl-CoA dehydrogenase deficiency (GDD) is an autosomal recessive disease characterized by the accumulation of glutaric and 3-hydroxyglutaric acids in tissues and body fluids. Untreated patients commonly present with severe striatal degeneration during encephalopathic crises. Previous studies have highlighted primary excitotoxicity as a trigger of striatal degeneration. The aim of this PhD study was to investigate in detail tissue-specific bioenergetic and biochemical parameters of GDD in vitro, post mortem, and in Gcdh-/- mice. The major bioenergetic finding was uncompetitive inhibition of alpha-ketoglutarate dehydrogenase complex by glutaryl-CoA. It is suggested that a synergism of primary and secondary excitotoxic effects in concert with age-related physiological changes in the developing brain underlie acute and chronic neurodegenerative changes in GDD patients. The major biochemical findings were highly elevated cerebral concentrations of glutaric and 3-hydroxyglutaric acid despite low permeability of the blood-brain barrier for these dicarboxylic acids. It can be postulated that glutaric and 3-hydroxyglutaric acids are synthesized de novo and subsequently trapped in the brain. In this light, neurological disease in GDD is not 'transported' to the brain in analogy with phenylketonuria or hepatic encephalopathy as suggested previously but is more likely to be induced by the intrinsic biochemical properties of the cerebral tissue and the blood-brain barrier.

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Glutaric Acid and Its Metabolites Cause Apoptosis in Immature Oligodendrocytes: A Novel Mechanism of White Matter Degeneration in Glutaryl-CoA Dehydrogenase Deficiency

Cited by 32 publications

References 31 publications

Kynurenic Acid Induces Impairment of Oligodendrocyte Viability: On the Role of Glutamatergic Mechanisms

Kynurenic Acid Induces Impairment of Oligodendrocyte Viability: On the Role of Glutamatergic Mechanisms

The sodium‐dependent di‐ and tricarboxylate transporter, NaCT, is not responsible for the uptake of D‐, L‐2‐hydroxyglutarate and 3‐hydroxyglutarate into neurons

Biochemistry and bioenergetics of glutaryl‐CoA dehydrogenase deficiency

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