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.
Highlights
Parkinson’s disease (PD) is an age-associated neurodegenerative disorder primarily caused by the progressive loss of dopaminergic (DA) neurons from the substantia nigra in the brain[1]
We identified 124 genes that were differentially regulated in response to PQ (Supplemental Table 1); these were enriched for biological processes (BP) that include innate immunity, oxidation-reduction, glutathione metabolic process, response to heat and response to nicotine based on Gene ontology (GO) analysis (Fig. 1a and Table 1)
Neuroinflammation is associated with several neurodegenerative diseases, including AD, PD, and multiple sclerosis (MS), that contribute to neuronal dysfunction and death[5]
Summary
Parkinson’s disease (PD) is an age-associated neurodegenerative disorder primarily caused by the progressive loss of dopaminergic (DA) neurons from the substantia nigra in the brain[1]. Administration of minocycline, a tetracycline derivative, effectively protects DA neurons in both mouse and Drosophila models by regulating the mitogen-activated protein kinase (MAPK) signaling pathways, which plays a critical role in controlling the expression of pro-inflammatory genes[12,13]. Over the last 15 years, investigations of neurodegenerative disease have incorporated invertebrate models such as Drosophila melanogaster and Caenorhabditis elegans on the principle that cellular and molecular mechanisms of neurodegeneration, metabolism, stress response and neuronal function are highly conserved[16,17,18] These models offer powerful genetic tools and short generation times to provide an entrée into genetic screens for identifying potentially important network components and cellular responses that may be validated in cell culture or in vivo mammalian models. Given the striking parallels of Drosophila and mammalian inflammatory responses during neurodegeneration, we postulated that controlled induction of neurodegeneration in Drosophila would be an entrée into the earliest cellular responses to neuron insult and that many of these responses will be conserved
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