title: A dopamine receptor contributes to paraquat-induced neurotoxicity in Drosophila.
abstract: Long-term exposure to environmental oxidative stressors, like the herbicide paraquat (PQ), has been linked to the development of Parkinson's disease (PD), the most frequent neurodegenerative movement disorder. Paraquat is thus frequently used in the fruit fly Drosophila melanogaster and other animal models to study PD and the degeneration of dopaminergic neurons (DNs) that characterizes this disease. Here, we show that a D1-like dopamine (DA) receptor, DAMB, actively contributes to the fast central nervous system (CNS) failure induced by PQ in the fly. First, we found that a long-term increase in neuronal DA synthesis reduced DAMB expression and protected against PQ neurotoxicity. Secondly, a striking age-related decrease in PQ resistance in young adult flies correlated with an augmentation of DAMB expression. This aging-associated increase in oxidative stress vulnerability was not observed in a DAMB-deficient mutant. Thirdly, targeted inactivation of this receptor in glutamatergic neurons (GNs) markedly enhanced the survival of Drosophila exposed to either PQ or neurotoxic levels of DA, whereas, conversely, DAMB overexpression in these cells made the flies more vulnerable to both compounds. Fourthly, a mutation in the Drosophila ryanodine receptor (RyR), which inhibits activity-induced increase in cytosolic Ca(2+), also strongly enhanced PQ resistance. Finally, we found that DAMB overexpression in specific neuronal populations arrested development of the fly and that in vivo stimulation of either DNs or GNs increased PQ susceptibility. This suggests a model for DA receptor-mediated potentiation of PQ-induced neurotoxicity. Further studies of DAMB signaling in Drosophila could have implications for better understanding DA-related neurodegenerative disorders in humans.
authors.affiliation: Genes Circuits Rhythms and Neuropathologies, Brain Plasticity Unit, CNRS, PSL Research University, ESPCI ParisTech, 10 rue Vauquelin, 75005 Paris, France.
authors.forename: Marlène
authors.initials: M
authors.lastname: Cassar
authors.affiliation: Genes Circuits Rhythms and Neuropathologies, Brain Plasticity Unit, CNRS, PSL Research University, ESPCI ParisTech, 10 rue Vauquelin, 75005 Paris, France.
authors.forename: Abdul-Raouf
authors.initials: AR
authors.lastname: Issa
authors.affiliation: Genes Circuits Rhythms and Neuropathologies, Brain Plasticity Unit, CNRS, PSL Research University, ESPCI ParisTech, 10 rue Vauquelin, 75005 Paris, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Riemensperger
authors.affiliation: Genes Circuits Rhythms and Neuropathologies, Brain Plasticity Unit, CNRS, PSL Research University, ESPCI ParisTech, 10 rue Vauquelin, 75005 Paris, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Petitgas
authors.affiliation: Genetics and Physiopathology of Neurotransmission, Developmental Biology Institute of Marseille-Luminy, CNRS, Université de la Méditerranée, 13009 Marseille, France and.
authors.forename: Thomas
authors.initials: T
authors.lastname: Rival
authors.affiliation: Genetics and Physiopathology of Neurotransmission, Developmental Biology Institute of Marseille-Luminy, CNRS, Université de la Méditerranée, 13009 Marseille, France and.
authors.forename: Hélène
authors.initials: H
authors.lastname: Coulom
authors.affiliation: Genetics and Physiopathology of Neurotransmission, Developmental Biology Institute of Marseille-Luminy, CNRS, Université de la Méditerranée, 13009 Marseille, France and.
authors.forename: Magali
authors.initials: M
authors.lastname: Iché-Torres
authors.affiliation: Department of Biological Sciences, Border Biomedical Research Center, University of Texas at El Paso, El Paso, TX 79968, USA.
authors.forename: Kyung-An
authors.initials: KA
authors.lastname: Han
authors.affiliation: Genes Circuits Rhythms and Neuropathologies, Brain Plasticity Unit, CNRS, PSL Research University, ESPCI ParisTech, 10 rue Vauquelin, 75005 Paris, France Genetics and Physiopathology of Neurotransmission, Developmental Biology Institute of Marseille-Luminy, CNRS, Université de la Méditerranée, 13009 Marseille, France and serge.birman@espci.fr.
authors.forename: Serge
authors.initials: S
authors.lastname: Birman
mesh_terms: D000367:Age Factors; D000818:Animals; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000378:metabolism*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000254:growth & development* / Q000378:metabolism; D004781:Environmental Exposure; D005260:Female; D006801:Humans; D020258:Neurotoxicity Syndromes / Q000378:metabolism*; D010269:Paraquat / Q000633:toxicity*; D010300:Parkinson Disease; D011954:Receptors, Dopamine; D017447:Receptors, Dopamine D1 / Q000378:metabolism*; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics
chemical_list: C093147:Dop1R1 protein, Drosophila; D029721:Drosophila Proteins; D011954:Receptors, Dopamine; D017447:Receptors, Dopamine D1; D019837:Ryanodine Receptor Calcium Release Channel; D010269:Paraquat; D004298:Dopamine