Inhibition of brain glutamate decarboxylase by glutarate, glutaconate, and β-Hydroxyglutarate: Explanation of the symptoms in glutaric aciduria?

Stokke, Oddvar; Goodman, Stephen I.; Moe, Paul G.

doi:10.1016/0009-8981(76)90241-2

Cited by 92 publications

(39 citation statements)

References 13 publications

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“…In cultured primary neuronal cells prepared from rat and chicken brains the activation of N-methyl-D-aspartate (NMDA) receptors has been reported upon incubation with GA and 3OHGA in vitro (3,4), which could not be confirmed in other studies (5,6). Furthermore, inhibition of ␥-aminobutyric acid (GABA) synthesis and the impairment of mitochondrial energy production due to inhibition of the ␣-ketoglutarate dehydrogenase complex and depletion of creatine phosphate are suggested to be relevant for neuronal death (3,4,(7)(8)(9). In addition, it has been shown that GA and 3OHGA impair the integrity of endothelial barriers in vitro and in vivo (10).…”

mentioning

confidence: 84%

Glutaric Aciduria Type 1 Metabolites Impair the Succinate Transport from Astrocytic to Neuronal Cells

Lamp

Keyser

Koeller

et al. 2011

Journal of Biological Chemistry

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The inherited neurodegenerative disorder glutaric aciduria type 1 (GA1) results from mutations in the gene for the mitochondrial matrix enzyme glutaryl-CoA dehydrogenase (GCDH), which leads to elevations of the dicarboxylates glutaric acid (GA) and 3-hydroxyglutaric acid (3OHGA) in brain and blood. The characteristic clinical presentation of GA1 is a sudden onset of dystonia during catabolic situations, resulting from acute striatal injury. The underlying mechanisms are poorly understood, but the high levels of GA and 3OHGA that accumulate during catabolic illnesses are believed to play a primary role. Both GA and 3OHGA are known to be substrates for Na

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mentioning

confidence: 84%

Glutaric Aciduria Type 1 Metabolites Impair the Succinate Transport from Astrocytic to Neuronal Cells

Lamp

Keyser

Koeller

et al. 2011

Journal of Biological Chemistry

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“…GABA levels may be initially reduced along with glutamate as brain glucose utilization is compromised during encephalopathy (37). Glutaric acid accumulation suppresses GABA production (21), and the return of glutamate levels with restored brain glucose utilization may set up unopposed excitatory neurotransmission resulting in seizures and excitotoxic lesions found in this model and in human GA-I (9). This possibility may explain the differences between glucose and homoarginine treatments and emphasizes the importance of controlling brain glutaric acid accumulation for neuroprotection.…”

Section: Figurementioning

confidence: 95%

Mechanism of age-dependent susceptibility and novel treatment strategy in glutaric acidemia type I

Zinnanti¹,

Lazović²,

Housman³

et al. 2007

J. Clin. Invest.

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Glutaric acidemia type I (GA-I) is an inherited disorder of lysine and tryptophan metabolism presenting with striatal lesions anatomically and symptomatically similar to Huntington disease. Affected children commonly suffer acute brain injury in the context of a catabolic state associated with nonspecific illness. The mechanisms underlying injury and age-dependent susceptibility have been unknown, and lack of a diagnostic marker heralding brain injury has impeded intervention efforts. Using a mouse model of GA-I, we show that pathologic events began in the neuronal compartment while enhanced lysine accumulation in the immature brain allowed increased glutaric acid production resulting in age-dependent injury. Glutamate and GABA depletion correlated with brain glutaric acid accumulation and could be monitored in vivo by proton nuclear magnetic resonance ( 1 H NMR) spectroscopy as a diagnostic marker. Blocking brain lysine uptake reduced glutaric acid levels and brain injury. These findings provide what we believe are new monitoring and treatment strategies that may translate for use in human GA-I.

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“…A direct or indirect activation of N-methyl-D-aspartate receptors was demonstrated in both in vitro and in vivo studies (13)(14)(15)(16). In support of this mechanism, a potential pathogenic role has been suggested for reduced glutamate uptake (17) and GABA production (18), Na ϩ /K ϩ -ATPase inhibition (19), and increased generation of reactive oxygen species (15,20) and nitric oxide (21) induced by these organic acids. However, some studies of cultured primary neurons were unable to confirm a role for glutamate receptor activation (22)(23)(24), suggesting that non-excitotoxic mechanisms, such as secondary inhibition of mitochondrial energy metabolism may be important.…”

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confidence: 92%

Bioenergetics in Glutaryl-Coenzyme A Dehydrogenase Deficiency

Sauer

Okun

Schwab

et al. 2005

Journal of Biological Chemistry

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111

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Inherited deficiency of glutaryl-CoA dehydrogenase results in an accumulation of glutaryl-CoA, glutaric, and 3-hydroxyglutaric acids. If untreated, most patients suffer an acute encephalopathic crisis and, subsequently, acute striatal damage being precipitated by febrile infectious diseases during a vulnerable period of brain development (age 3 and 36 months). It has been suggested before that some of these organic acids may induce excitotoxic cell damage, however, the relevance of bioenergetic impairment is not yet understood. The major aim of our study was to investigate respiratory chain, tricarboxylic acid cycle, and fatty acid oxidation in this disease using purified single enzymes and tissue homogenates from Gcdh-deficient and wild-type mice. In purified enzymes, glutaryl-CoA but not glutaric or 3-hydroxyglutaric induced an uncompetitive inhibition of ␣-ketoglutarate dehydrogenase complex activity. Notably, reduced activity of ␣-ketoglutarate dehydrogenase activity has recently been demonstrated in other neurodegenerative diseases, such as Alzheimer, Parkinson, and Huntington diseases. In contrast to ␣-ketoglutarate dehydrogenase complex, no direct inhibition of glutaryl-CoA, glutaric acid, and 3-hydroxyglutaric acid was found in other enzymes tested. In Gcdh-deficient mice, respiratory chain and tricarboxylic acid activities remained widely unaffected, virtually excluding regulatory changes in these enzymes. However, hepatic activity of very long-chain acyl-CoA dehydrogenase was decreased and concentrations of long-chain acylcarnitines increased in the bile of these mice, which suggested disturbed oxidation of long-chain fatty acids. In conclusion, our results demonstrate that bioenergetic impairment may play an important role in the pathomechanisms underlying neurodegenerative changes in glutaryl-CoA dehydrogenase deficiency.

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Inhibition of brain glutamate decarboxylase by glutarate, glutaconate, and β-Hydroxyglutarate: Explanation of the symptoms in glutaric aciduria?

Cited by 92 publications

References 13 publications

Glutaric Aciduria Type 1 Metabolites Impair the Succinate Transport from Astrocytic to Neuronal Cells

Glutaric Aciduria Type 1 Metabolites Impair the Succinate Transport from Astrocytic to Neuronal Cells

Mechanism of age-dependent susceptibility and novel treatment strategy in glutaric acidemia type I

Bioenergetics in Glutaryl-Coenzyme A Dehydrogenase Deficiency

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