title: Genetic activation of Nrf2 signaling is sufficient to ameliorate neurodegenerative phenotypes in a Drosophila model of Parkinson's disease.
abstract: 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.
authors: Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors: Maria Cecilia
authors: MC
authors: Barone
authors: Gerasimos P
authors: GP
authors: Sykiotis
authors: Dirk
authors: D
authors: Bohmann
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000378:metabolism / Q000473:pathology; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D004331:Drosophila melanogaster / Q000187:drug effects / Q000235:genetics*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D000072019:Kelch-Like ECH-Associated Protein 1; D008124:Locomotion / Q000187:drug effects; D051267:NF-E2-Related Factor 2 / Q000235:genetics* / Q000378:metabolism; D009410:Nerve Degeneration / Q000150:complications / Q000235:genetics / Q000473:pathology*; D010300:Parkinson Disease / Q000150:complications / Q000235:genetics / Q000473:pathology*; D010641:Phenotype; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*; D015533:Transcriptional Activation / Q000187:drug effects; D019076:Transgenes / Q000235:genetics; D051844:alpha-Synuclein / Q000633:toxicity
chemical_list: D029721:Drosophila Proteins; D047908:Intracellular Signaling Peptides and Proteins; C527886:Keap1 protein, Drosophila; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; D051844:alpha-Synuclein