Abnormal Glutamate Metabolism in an Adult-Onset Degenerative Neurological Disorder

Plaitakis, Andreas; Berl, S.; Yahr,

doi:10.1126/science.6121377

Cited by 228 publications

(92 citation statements)

References 17 publications

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“…Because of its neuroexcitotoxic potentials (8), glutamate may be involved in the pathogenesis of certain human heredodegenerations (9) or may mediate neuronal damage in response to various metabolic insults (10,11). Evidence implicating a direct role of GLUD in the pathogenesis of human degenerative disorders has been suggested by recent studies showing decreased activity of the enzyme and abnormal glutamate metabolism in patients with neurological disorders characterized by multisystem atrophy (3,12). Further studies have indicated that two distinct forms of GLUD may exist in human tissues and rat brain (12,13).…”

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confidence: 95%

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Isolation and characterization of cDNA clones encoding human liver glutamate dehydrogenase: evidence for a small gene family.

Mavrothalassitis

Tzimagiorgis

Mitsialis

et al. 1988

Proc. Natl. Acad. Sci. U.S.A.

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We have isolated a series of human liver cDNA clones encoding glutamate dehydrogenase. The cDNAderived protein sequence specifies a single 558-amino acid long polypeptide including a cleavable signal sequence of 53 amino acids. Blotting analysis of RNA from human, monkey, and rabbit showed that glutamate dehydrogenase mRNA is present in various amounts in all tissues tested. Glutamate dehydrogenase mRNAs are of four sizes and are found in different ratios in different tissues; the predominant ones are ".3.5 and =2.9 kilobases. Blot hybridization of human genomic DNA to nonoverlapping cDNA fragments revealed multiple bands, many of which hybridize with two or more probes in a manner inconsistent with the existence of a single GLUD gene. Moreover, two separate 36-base synthetic oligonucleotides corresponding to the coding region hybridize to multiple genomic fragments, confirming the existence of more than one GLUDrelated gene in human.

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confidence: 95%

“…Substantial amounts of GLUD activity are known to be present in different mammalian organs such as liver and brain and in leukocytes (1,2). Evidence has been accumulated in recent years to suggest that GLUD is of importance in the biology of the nervous tissue and the pathogenesis of human neurodegenerative disorders (2,3).…”

mentioning

confidence: 99%

Isolation and characterization of cDNA clones encoding human liver glutamate dehydrogenase: evidence for a small gene family.

Mavrothalassitis

Tzimagiorgis

Mitsialis

et al. 1988

Proc. Natl. Acad. Sci. U.S.A.

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“…Current studies showed the presence of four different sized mRNA and multiple gene copies for GDH in the human brain [9,10,22,231. A partial deficiency of GDH has been reported in fibroblasts and leukocytes of humans with olivopontocerebellar atrophy [3,241. Two forms of GDH may be present in leukocytes, and the deficiencies may be limited to one of the two 141.…”

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confidence: 99%

Two Soluble forms of Glutamate Dehydrogenase Isoproteins from Bovine Brain

Cho

Lee

Choi

1995

European Journal of Biochemistry

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Two soluble forms of novel glutamate dehydrogenase isoproteins, designated GDH I and GDH 11, have been purified from bovine brain. GDH I and GDH I1 were separated on a hydroxyapatite column and eluted by a step gradient at different phosphate concentrations (30 mM and 50 rnM for GDH I and GDH 11, respectively). The preparations were homogeneous on SDS/PAGE. GDH I and GDH II showed similarity in their molecular sizes and are composed of six identical subunits having a molecular size of 57500 Da. Differences between the biochemical properties of GDH I and GDH 11, such as N-terminal amino acid sequences of intact and tryptic-digested enzymes, kinetic parameters, optimum pH and heat stability, were extensively examined in both reductive amination of a-oxoglutarate and oxidative deamination of glutamate. The different effects of ADP on GDH isoproteins were also studied under various conditions. These results indicate that GDH I and GDH 11, isolated from bovine brain, are novel and distinct polypeptides.

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“…Abnormalities in glutamate metabolism have been reported in patients with neurodegenerative disorders, 8 including PD, 9 raising the possibility that metabolic defects involving this amino acid might be operational. Some of these patients had altered activities and increased thermal stability of glutamate dehydrogenase (GDH), 10 a mitochondrial enzyme expressed in midbrain dopaminergic neurons 11 that catalyzes glutamate oxidation.…”

Section: Introductionmentioning

confidence: 99%

Gain-of-function variant in GLUD2 glutamate dehydrogenase modifies Parkinson's disease onset

et al. 2009

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Parkinson's disease (PD), a common neurodegenerative disorder characterized by progressive loss of dopaminergic neurons and their terminations in the basal ganglia, is thought to be related to genetic and environmental factors. Although the pathophysiology of PD neurodegeneration remains unclear, protein misfolding, mitochondrial abnormalities, glutamate dysfunction and/or oxidative stress have been implicated. In this study, we report that a rare T1492G variant in GLUD2, an X-linked gene encoding a glutamate dehydrogenase (a mitochondrial enzyme central to glutamate metabolism) that is expressed in brain (hGDH2), interacted significantly with age at PD onset in Caucasian populations. Individuals hemizygous for this GLUD2 coding change that results in substitution of Ala for Ser445 in the regulatory domain of hGDH2 developed PD 6-13 years earlier than did subjects with other genotypes in two independent Greek PD groups and one North American PD cohort. However, this effect was not present in female PD patients who were heterozygous for the DNA change. The variant enzyme, obtained by substitution of Ala for Ser445, showed an enhanced basal activity that was resistant to GTP inhibition but markedly sensitive to modification by estrogens. Thus, a gain-of-function rare polymorphism in hGDH2 hastens the onset of PD in hemizygous subjects, probably by damaging nigral cells through enhanced glutamate oxidative dehydrogenation. The lack of effect in female heterozygous PD patients could be related to a modification of the overactive variant enzyme by estrogens. INTRODUCTIONParkinson's disease (PD) affects about 1.8% of people over the age of 65 years. 1 It is clinically characterized by tremor, rigidity and bradykinesia, which often occur along with disturbances of posture and gait. 2 About 80% of PD cases are sporadic, with males being more frequently affected than females (ratio¼1.5:1).The etiology of PD remains largely unknown, although interplay of environmental toxins with genetic susceptibility may be operational. The genetic hypothesis is supported by community-based studies showing that a substantial number of PD patients have similarly affected relatives. 3,4 This was also revealed by a PD study conducted by us on Crete, 5 an island of about 0.6 million people sharing the same genetic and cultural background and a common environment. Moreover, this study suggested an oligogenic model for PD, according to which disease-predisposing alleles from two or more genes need to be present in the same individual for the disorder to be expressed.With regard to the pathophysiology of PD, several hypotheses have been proposed in an attempt to explain the degeneration of dopaminergic neurons in this disorder. One of these suggests that mitochondrial dysfunction is involved, 6 a contention supported by the recent discovery of monogenetic forms of PD resulting from mutations of

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Abnormal Glutamate Metabolism in an Adult-Onset Degenerative Neurological Disorder

Cited by 228 publications

References 17 publications

Isolation and characterization of cDNA clones encoding human liver glutamate dehydrogenase: evidence for a small gene family.

Isolation and characterization of cDNA clones encoding human liver glutamate dehydrogenase: evidence for a small gene family.

Two Soluble forms of Glutamate Dehydrogenase Isoproteins from Bovine Brain

Gain-of-function variant in GLUD2 glutamate dehydrogenase modifies Parkinson's disease onset

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