title: Synergistic effects on dopamine cell death in a Drosophila model of chronic toxin exposure.
abstract: The neurodegenerative effects of Parkinson's disease (PD) are marked by a selective loss of dopaminergic (DA) neurons. Epidemiological studies suggest that chronic exposure to the pesticide paraquat may increase the risk for PD and DA cell loss. However, combined exposure with additional fungicide(s) including maneb and/or ziram may be required for pathogenesis. To explore potential pathogenic mechanisms, we have developed a Drosophila model of chronic paraquat exposure. We find that while chronic paraquat exposure alone decreased organismal survival and motor function, combined chronic exposure to both paraquat and maneb was required for DA cell death in the fly. To initiate mechanistic studies of this interaction, we used additional genetic reagents to target the ubiquitin proteasome system, which has been implicated in some rare familial forms of PD and the toxic effects of ziram. Genetic inhibition of E1 ubiquitin ligase, but not the proteasome itself, increased DA cell death in combination with maneb but not paraquat. These studies establish a model for long-term exposure to multiple pesticides, and support the idea that pesticide interactions relevant to PD may involve inhibition of protein ubiquitination.
authors.affiliation: UCLA Interdepartmental Program in Molecular Toxicology, Los Angeles, CA 90095, United States. Electronic address: martin.ciaraann@gmail.com.
authors.forename: Ciara A
authors.initials: CA
authors.lastname: Martin
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, The Gonda (Goldschmied) Neuroscience and Genetics Research Center, Room 3335, Hatos Center For Neuropharmacology, David Geffen School of Medicine, University of California Los Angeles, 695 Charles E. Young Drive South, Los Angeles, CA 90095, United States. Electronic address: a.barajas40@gmail.com.
authors.forename: Angel
authors.initials: A
authors.lastname: Barajas
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, The Gonda (Goldschmied) Neuroscience and Genetics Research Center, Room 3335, Hatos Center For Neuropharmacology, David Geffen School of Medicine, University of California Los Angeles, 695 Charles E. Young Drive South, Los Angeles, CA 90095, United States. Electronic address: glawless@ucla.edu.
authors.forename: George
authors.initials: G
authors.lastname: Lawless
authors.affiliation: UCLA Interdepartmental Program in Molecular Toxicology, Los Angeles, CA 90095, United States; Department of Psychiatry and Biobehavioral Sciences, The Gonda (Goldschmied) Neuroscience and Genetics Research Center, Room 3335, Hatos Center For Neuropharmacology, David Geffen School of Medicine, University of California Los Angeles, 695 Charles E. Young Drive South, Los Angeles, CA 90095, United States. Electronic address: hakeemlawal@gmail.com.
authors.forename: Hakeem O
authors.initials: HO
authors.lastname: Lawal
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, The Gonda (Goldschmied) Neuroscience and Genetics Research Center, Room 3335, Hatos Center For Neuropharmacology, David Geffen School of Medicine, University of California Los Angeles, 695 Charles E. Young Drive South, Los Angeles, CA 90095, United States. Electronic address: khadij.assani@gmail.com.
authors.forename: Khadij
authors.initials: K
authors.lastname: Assani
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, The Gonda (Goldschmied) Neuroscience and Genetics Research Center, Room 3335, Hatos Center For Neuropharmacology, David Geffen School of Medicine, University of California Los Angeles, 695 Charles E. Young Drive South, Los Angeles, CA 90095, United States. Electronic address: y.lumintang@yahoo.com.
authors.forename: Yosephine P
authors.initials: YP
authors.lastname: Lumintang
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, The Gonda (Goldschmied) Neuroscience and Genetics Research Center, Room 3335, Hatos Center For Neuropharmacology, David Geffen School of Medicine, University of California Los Angeles, 695 Charles E. Young Drive South, Los Angeles, CA 90095, United States. Electronic address: vnunez16@ucla.edu.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Nunez
authors.affiliation: UCLA Interdepartmental Program in Molecular Toxicology, Los Angeles, CA 90095, United States; Department of Psychiatry and Biobehavioral Sciences, The Gonda (Goldschmied) Neuroscience and Genetics Research Center, Room 3335, Hatos Center For Neuropharmacology, David Geffen School of Medicine, University of California Los Angeles, 695 Charles E. Young Drive South, Los Angeles, CA 90095, United States. Electronic address: dkrantz@ucla.edu.
authors.forename: David E
authors.initials: DE
authors.lastname: Krantz
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000378:metabolism; D004331:Drosophila melanogaster; D008344:Maneb / Q000633:toxicity*; D009043:Motor Activity / Q000187:drug effects; D010269:Paraquat / Q000633:toxicity*; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000378:metabolism; D010575:Pesticides / Q000633:toxicity*; D016019:Survival Analysis; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D015039:Ziram / Q000633:toxicity*
chemical_list: D010575:Pesticides; D008344:Maneb; D015039:Ziram; D044767:Ubiquitin-Protein Ligases; D010269:Paraquat
keywords: E1 ligase; Maneb; Paraquat; Parkinson's disease; Ubiquitin proteasome system; Ziram