TY - JOUR
T1 - Gain-of-function variant in GLUD2 glutamate dehydrogenase modifies Parkinson's disease onset
AU - Plaitakis, Andreas
AU - Latsoudis, Helen
AU - Kanavouras, Konstantinos
AU - Ritz, Beate
AU - Bronstein, Jeff M.
AU - Skoula, Irene
AU - Mastorodemos, Vasileios
AU - Papapetropoulos, Spyridon
AU - Borompokas, Nikolas
AU - Zaganas, Ioannis
AU - Xiromerisiou, Georgia
AU - Hadjigeorgiou, George M.
AU - Spanaki, Cleanthe
N1 - Funding Information:
This study was supported by the Association for Research and Treatment of Neurologic Disorders of Crete (EY-ZHN) and by the Second Operational Programme for Education and Initial Vocational Training (EPEAEK II) to HL and CS from the Ministry of Education of Greece. We are grateful to PD patients and their families for participating in this study. We also thank Mrs M Rogdaki for her help in genetic studies.
PY - 2010/3
Y1 - 2010/3
N2 - 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.
AB - 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.
KW - Estrogens
KW - Gain-of-function
KW - Glutamate dehydrogenase
KW - Parkinson's disease onset
UR - http://www.scopus.com/inward/record.url?scp=77149147406&partnerID=8YFLogxK
U2 - 10.1038/ejhg.2009.179
DO - 10.1038/ejhg.2009.179
M3 - Article
C2 - 19826450
AN - SCOPUS:77149147406
SN - 1018-4813
VL - 18
SP - 336
EP - 341
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
IS - 3
ER -