Neuroprotection by Transgenic Expression of Glucose-6-Phosphate Dehydrogenase in Dopaminergic Nigrostriatal Neurons of Mice

Oxidative damage to dopaminergic nigrostriatal (DNS) neurons plays a central role in the pathogenesis of Parkinson's disease (PD). Glucose-6-phosphate dehydrogenase (G6PD) is a key cytoprotective enzyme that provides NADPH, the major source of the reducing equivalents of a cell. Mutations of th...

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Bibliographic Details
Published in:The Journal of neuroscience 2006-04, Vol.26 (17), p.4500-4508
Main Authors: Mejias, Rebeca, Villadiego, Javier, Pintado, C. Oscar, Vime, Pablo J, Gao, Lin, Toledo-Aral, Juan J, Echevarria, Miriam, Lopez-Barneo, Jose
Format: Article
Language:English
Subjects:
Animals
Animals, Genetically Modified
Cells, Cultured
Corpus Striatum - metabolism
Corpus Striatum - pathology
Dopamine - metabolism
Glucosephosphate Dehydrogenase - genetics
Glucosephosphate Dehydrogenase - metabolism
Mice - genetics
Neuroprotective Agents - metabolism
Parkinsonian Disorders - metabolism
Parkinsonian Disorders - pathology
Recombinant Proteins - metabolism
Substantia Nigra - metabolism
Substantia Nigra - pathology
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Summary:Oxidative damage to dopaminergic nigrostriatal (DNS) neurons plays a central role in the pathogenesis of Parkinson's disease (PD). Glucose-6-phosphate dehydrogenase (G6PD) is a key cytoprotective enzyme that provides NADPH, the major source of the reducing equivalents of a cell. Mutations of this enzyme are the most common enzymopathies worldwide. We have studied in vivo the role of G6PD overexpressed specifically in the DNS pathway and show that the increase of G6PD activity in the soma and axon terminals of DNS neurons, separately from other neurons or glial cells, protects them from parkinsonism. Analysis of DNS neurons by histological, neurochemical, and functional methods showed that even a moderate increase of G6PD activity rendered transgenic mice more resistant than control littermates to the toxic effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The neuroprotective action of G6PD was also observed in aged animals despite that they had a greater susceptibility to MPTP. Therefore, overexpression of G6PD in dopaminergic neurons or pharmacological activation of the native enzyme should be considered as potential therapeutic strategies to PD.
ISSN:0270-6474
1529-2401
DOI:10.1523/JNEUROSCI.0122-06.2006