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The Journal of Neuroscience, April 26, 2006, 26(17):4500-4508; doi:10.1523/JNEUROSCI.0122-06.2006

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

Rebeca Mejías,1 Javier Villadiego,1 C. Oscar Pintado,2 Pablo J. Vime,1 Lin Gao,1 Juan J. Toledo-Aral,1 Miriam Echevarría,1 and José López-Barneo1

1Laboratorio de Investigaciones Biomédicas, Hospital Universitario Virgen del Rocío, E-41013 Sevilla, Spain, and 2Centro de Producción y Experimentación Animal, Universidad de Sevilla, LE-41807 Sevilla, Spain

Correspondence should be addressed to Dr. José López-Barneo, Laboratorio de Investigaciones Biomédicas, Edificio de Laboratorios, 2a planta, Hospital Universitario Virgen del Rocío, Avenida Manuel Siurot s/n, E-41013, Sevilla, Spain. Email: jose.l.barneo.sspa{at}juntadeandalucia.es

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.

Key words: dopaminergic nigrostriatal neurons; glucose-6-phosphate dehydrogenase; transgenic mice; neurodegeneration; experimental parkinsonism; gene therapy

Received July 19, 2005; revised Feb. 18, 2006; accepted March 12, 2006.

Correspondence should be addressed to Dr. José López-Barneo, Laboratorio de Investigaciones Biomédicas, Edificio de Laboratorios, 2a planta, Hospital Universitario Virgen del Rocío, Avenida Manuel Siurot s/n, E-41013, Sevilla, Spain. Email: jose.l.barneo.sspa{at}juntadeandalucia.es






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