1. ¹Department of Neurology, Medical School, University of Crete, Heraklion, Crete, Greece
2. ²Department of Epidemiology, School of Public Health, University of California, Los Angeles, CA, USA
3. ³Department of Neurology, University of California at Los Angeles David Geffen School of Medicine, Los Angeles, CA, USA
4. ⁴Division of Movement Disorders, Department of Neurology, Miller School of Medicine, University of Miami, Miami, FL, USA
5. ⁵Department of Neurology, Medical School of Larissa, University of Thessaly, Larissa, Greece

Correspondence: Professor A Plaitakis, Department of Neurology, Medical School, University of Crete, Voutes and Staurakia, 71003 Heraklion, Crete, Greece. Tel: +30 2810 394648; Fax: +30 2810 394648; E-mail: plaitak@med.uoc.gr

Received 27 April 2009; Revised 16 July 2009; Accepted 9 September 2009; Published online 14 October 2009.

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.