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, 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.

Auxilin Underlies Progressive Locomotor Deficits and Dopaminergic Neuron Loss in a Drosophila Model of Parkinson’s Disease

“…aux Expression Alters Paraquat Susceptibility in Flies Multiple lines of evidence have established that the application of environmental toxin paraquat induces PD-implicated symptoms in Drosophila (Martin et al, 2014;Navarro et al, 2014;Shukla et al, 2016). Based on these studies, wild-type w 1118 flies were first exposed to different paraquat concentrations (1, 5, 10, and 20 mM), and surviving flies were analyzed at different time points up to 120 hr (Martin et al, 2014;Navarro et al, 2014;Shukla et al, 2016). Interestingly, the proportion of surviving flies is concentration dependent, with 5 mM paraquat manifesting the intermediate survival level (Figure S3C).…”

Drosophila Models of Sporadic Parkinson’s Disease

“…In flies, chronic exposure to either 4 mM paraquat, 500 μM maneb, or 1mM ziram (the dose that does not decrease survival) does not individually impair DA neuron viability or climbing ability. In contrast, the combined exposure of paraquat and maneb, but not paraquat and ziram, leads to DA neuron loss in the PPL1 cluster at 6 weeks [42,49].…”

Ziram, a pesticide associated with increased risk for Parkinson's disease, differentially affects the presynaptic function of aminergic and glutamatergic nerve terminals at the Drosophila neuromuscular junction

“…However, an increase in evoked exocytosis seen in Type I terminals would be expected to cause an increase in glutamate release, and similar effects in the CNS could also lead to an increase in the excitation of downstream circuits. Future experiments to directly test these hypotheses and the effects of ziram exposure in fly as a whole may require parenteral administration; but it has proven difficult to administer neurotoxic doses of ziram through feeding (Martin et al, 2014). …”

“…Flies expressing E1 RNAi and DVMAT-pHluorin were generated as described in (Martin et al, 2014) and (Grygoruk et al, 2014), respectively, and are available on request. Other lines including elav-GAL4(X) (Robinow and White, 1991), Tdc2-GAL4 (Cole et al, 2005), DVGLUT-GAL4 (Daniels et al, 2004), UAS-Arclight (Cao et al, 2013) and UAS-GCaMP6m(III) (Chen et al, 2013) are available from the Bloomington Stock Center.…”