Gain-of-function variant in GLUD2 glutamate dehydrogenase modifies Parkinson's disease onset.
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.
Plaitakis
Andreas
A
Department of Neurology, Medical School, University of Crete, Heraklion, Crete, Greece. plaitak@med.uoc.gr
Latsoudis
Helen
H
Kanavouras
Konstantinos
K
Ritz
Beate
B
Bronstein
Jeff M
JM
Skoula
Irene
I
Mastorodemos
Vasileios
V
Papapetropoulos
Spyridon
S
Borompokas
Nikolas
N
Zaganas
Ioannis
I
Xiromerisiou
Georgia
G
Hadjigeorgiou
George M
GM
Spanaki
Cleanthe
C
D000244:Adenosine Diphosphate / Q000494:pharmacology; D017668:Age of Onset; D000368:Aged; D055162:Biocatalysis / Q000187:drug effects; D002140:California / Q000453:epidemiology; D015331:Cohort Studies; D003710:Demography; D004054:Diethylstilbestrol / Q000494:pharmacology; D005260:Female; D005969:Glutamate Dehydrogenase / Q000235:genetics*; D006115:Greece / Q000453:epidemiology; D006160:Guanosine Triphosphate / Q000494:pharmacology; D006801:Humans; D007930:Leucine / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease / Q000201:enzymology* / Q000453:epidemiology / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011994:Recombinant Proteins / Q000378:metabolism
D011994:Recombinant Proteins; D000244:Adenosine Diphosphate; D004054:Diethylstilbestrol; D006160:Guanosine Triphosphate; D005969:Glutamate Dehydrogenase; C521120:GLUD2 protein, human; D007930:Leucine