Genetic activation of Nrf2 signaling is sufficient to ameliorate neurodegenerative phenotypes in a Drosophila model of Parkinson's disease.

Détails

ID Serval
serval:BIB_F8877F11664B
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Genetic activation of Nrf2 signaling is sufficient to ameliorate neurodegenerative phenotypes in a Drosophila model of Parkinson's disease.
Périodique
Disease Models and Mechanisms
Auteur(s)
Barone M.C., Sykiotis G.P., Bohmann D.
ISSN
1754-8411 (Electronic)
ISSN-L
1754-8403
Statut éditorial
Publié
Date de publication
2011
Peer-reviewed
Oui
Volume
4
Numéro
5
Pages
701-707
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural Publication Status: ppublish
Résumé
Parkinson's disease (PD) is the most common neurodegenerative movement disorder. Oxidative stress has been associated with the etiology of both sporadic and monogenic forms of PD. The transcription factor Nrf2, a conserved global regulator of cellular antioxidant responses, has been implicated in neuroprotection against PD pathology. However, direct evidence that upregulation of the Nrf2 pathway is sufficient to confer neuroprotection in genetic models of PD is lacking. Expression of the PD-linked gene encoding α-synuclein in dopaminergic neurons of Drosophila results in decreased locomotor activity and selective neuron loss in a progressive age-dependent manner, providing a genetically accessible model of PD. Here we show that upregulation of the Nrf2 pathway by overexpressing Nrf2 or its DNA-binding dimerization partner, Maf-S, restores the locomotor activity of α-synuclein-expressing flies. Similar benefits are observed upon RNA-interference-mediated downregulation of the prime Nrf2 inhibitor, Keap1, as well as in conditions of keap1 heterozygosity. Consistently, the α-synuclein-induced dopaminergic neuron loss is suppressed by Maf-S overexpression or keap1 heterozygosity. Our data validate the sustained upregulation of the Nrf2 pathway as a neuroprotective strategy against PD. This model provides a genetically accessible in vivo system in which to evaluate the potential of additional Nrf2 pathway components and regulators as therapeutic targets.
Mots-clé
Animals, Disease Models, Animal, Dopaminergic Neurons/metabolism, Dopaminergic Neurons/pathology, Drosophila Proteins/genetics, Drosophila Proteins/metabolism, Drosophila melanogaster/drug effects, Drosophila melanogaster/genetics, Intracellular Signaling Peptides and Proteins/metabolism, Locomotion/drug effects, NF-E2-Related Factor 2/genetics, NF-E2-Related Factor 2/metabolism, Nerve Degeneration/complications, Nerve Degeneration/genetics, Parkinson Disease/complications, Parkinson Disease/genetics, Phenotype, Signal Transduction/drug effects, Signal Transduction/genetics, Transcriptional Activation/drug effects, Transgenes/genetics, alpha-Synuclein/toxicity
Pubmed
Web of science
Open Access
Oui
Création de la notice
20/01/2015 14:40
Dernière modification de la notice
20/08/2019 17:24
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