Innate immune responses to paraquat exposure in a Drosophila model of Parkinson’s disease

Abstract

Parkinson’s disease (PD) is a progressive, neurodegenerative movement disorder characterized by the loss of dopaminergic (DA) neurons. Limited understanding of the early molecular pathways associated with the demise of DA neurons, including those of inflammatory exacerbation of neurodegeneration, is a major impediment to therapeutic development. Recent studies have implicated gene-environment interactions in PD susceptibility. We used transcriptomic profiling in a Drosophila PD model in response to paraquat (PQ)-induced oxidative stress to identify pre-symptomatic signatures of impending neuron dysfunction. Our RNAseq data analysis revealed extensive regulation of innate immune response genes following PQ ingestion. We found that PQ exposure leads to the activation of the NF-κB transcription factor, Relish, and the stress signaling factor JNK, encoded by the gene basket in Drosophila . Relish knockdown in the dopaminergic neurons confers PQ resistance and rescues mobility defects and DA neuron loss. Furthermore, PQ-induced toxicity is mediated through the immune deficiency signaling pathway. Surprisingly, the expression of Relish-dependent anti-microbial peptide (AMPs) genes is suppressed upon PQ exposure causing increased sensitivity to Gram-negative bacterial infection. This work provides a novel link between PQ exposure and innate immune system modulation underlying environmental toxin-induced neurodegeneration, thereby underscoring the role of the innate immune system in PD pathogenesis.

GardeninA confers neuroprotection against environmental toxin in a Drosophila model of Parkinson’s disease

“…We have previously shown that exposure to the herbicide, paraquat (PQ) significantly reduces survival and impairs climbing abilities in the wild-type Drosophila strain, Canton S 6,31 . We employed an environmental toxin-induced model in Drosophila, that recapitulates the behavioral and pathological symptoms of PD, as a screening platform to identify phytochemicals with therapeutic potential against PQ toxicity using the feeding regimen shown in Fig.…”

“…Paraquat has been shown to induce the loss of specific clusters of dopaminergic neurons in both mammalian and Drosophila PD models 6,31 . Since GA pretreatment improved PQ-induced mobility defects, we analyzed the effect of GA and GB on specific clusters of dopaminergic (DA) neurons in the adult Drosophila brain.…”

“…In addition to genetic mutations, numerous epidemiological studies have strongly indicated that occupational exposure to environmental toxins, such as pesticides like paraquat (PQ), rotenone, or neurotoxic metals, is associated with a higher risk of developing idiopathic PD 4,5 . Exposure to PQ is known to induce oxidative stress and mimic clinical signs similar to PD, including reduced motor function and selective dopamine neuron degeneration, which can be rescued by administration of L-dopa in both mammalian and Drosophila models 6,7 . A recent study has demonstrated the link between PQ exposure and PD using human stem cells 8 .…”

“…A recent study has demonstrated the link between PQ exposure and PD using human stem cells 8 . Moreover, our recently published data using transcriptomic analysis identified genes in Drosophila PD model, whose mammalian orthologs are implicated in PD pathogenesis 6 . PQ has also been shown to induce dysregulated inflammatory responses related to neuronal cell death 6 .…”

“…Moreover, our recently published data using transcriptomic analysis identified genes in Drosophila PD model, whose mammalian orthologs are implicated in PD pathogenesis 6 . PQ has also been shown to induce dysregulated inflammatory responses related to neuronal cell death 6 . Both oxidative stress and neuroinflammation have been associated with PD pathogenesis in both mammalian and Drosophila models 9 .…”