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

Abstract

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

Estrogen Actions in the Brain and the Basis for Differential Action in Men and Women: A Case for Sex-Specific Medicines

“…In hemizygous male subjects, it has been speculated that this might be due to enhanced glutamate oxidative phosphorylation in dopaminergic neurons. It is noteworthy that there was no association in heterozygous female patients with PD, which was attributable to the finding that estrogens suppress enzyme activity (Plaitakis et al, 2010).…”

Estrogen Modification of Human Glutamate Dehydrogenases Is Linked to Enzyme Activation State

“…These observations, taken together with recent findings showing that overexpression of GDH1 in mice results in age-dependent degenerative changes in the CA1 region of the hippocampus (34), suggest that a tight regulation of GDH activity is of importance for nerve tissue function and degeneration. Regarding deregulation of hGDH2 in human disorders, recent studies revealed that patients with Parkinson disease, who were hemizygous for T1492G polymorphism in the GLUD2 gene, experienced onset of their disease 8 -13 years earlier than patients with other genotypes in two populations of diverse genetic background (35). However, female Parkinson disease patients who were heterozygous for this allele were protected.…”

“…However, female Parkinson disease patients who were heterozygous for this allele were protected. The T1492G polymorphism is within the coding region of the GLUD2 gene and results in the substitution of Ala for Ser 445 in the regulatory domain of hGDH2 (35). The S445A variant, obtained in recombinant form by expressing the T1492G-GLUD2 cDNA in Sf21 cells, displayed enhanced basal activity that was sensitive to inhibition by estrogens (35).…”

“…The S445A variant, obtained in recombinant form by expressing the T1492G-GLUD2 cDNA in Sf21 cells, displayed enhanced basal activity that was sensitive to inhibition by estrogens (35). As such, the protection of female heterozygotes (for T1492G polymorphism) from the gain-of-function properties of the S445A hGDH2 variant has been attributed to estrogen inhibition of the overactive enzyme (35). Also, independent studies have provided evidence that female hormones protect from Parkinson disease (36) and that apoptosis of dopaminergic neurons occurs in aromatase knock-out mice in the male (37).…”

“…The T1492G polymorphism is within the coding region of the GLUD2 gene and results in the substitution of Ala for Ser 445 in the regulatory domain of hGDH2 (35). The S445A variant, obtained in recombinant form by expressing the T1492G-GLUD2 cDNA in Sf21 cells, displayed enhanced basal activity that was sensitive to inhibition by estrogens (35). As such, the protection of female heterozygotes (for T1492G polymorphism) from the gain-of-function properties of the S445A hGDH2 variant has been attributed to estrogen inhibition of the overactive enzyme (35).…”