Neuroprotection by transgenic expression of glucose-6-phosphate dehydrogenase in dopaminergic nigrostriatal neurons of mice

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

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)4500-4508
Number of pages9
JournalJournal of Neuroscience
Volume26
Issue number17
DOIs
StatePublished - 2006

Keywords

  • Dopaminergic nigrostriatal neurons
  • Experimental parkinsonism
  • Gene therapy
  • Glucose-6-phosphate dehydrogenase
  • Neurodegeneration
  • Transgenic mice

ASJC Scopus subject areas

  • Neuroscience(all)

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