Synergistic effects on dopamine cell death in a Drosophila model of chronic toxin exposure

Neurotoxicology. 2014 Sep;44:344-51. doi: 10.1016/j.neuro.2014.08.005. Epub 2014 Aug 23.

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.

Keywords: E1 ligase; Maneb; Paraquat; Parkinson's disease; Ubiquitin proteasome system; Ziram.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Death / drug effects
  • Disease Models, Animal
  • Dopaminergic Neurons / drug effects*
  • Dopaminergic Neurons / metabolism
  • Drosophila melanogaster
  • Maneb / toxicity*
  • Motor Activity / drug effects
  • Paraquat / toxicity*
  • Parkinson Disease, Secondary / chemically induced
  • Parkinson Disease, Secondary / metabolism
  • Pesticides / toxicity*
  • Survival Analysis
  • Ubiquitin-Protein Ligases / metabolism
  • Ziram / toxicity*

Substances

  • Pesticides
  • Maneb
  • Ziram
  • Ubiquitin-Protein Ligases
  • Paraquat