Objective: To identify the genetic basis and the molecular mechanisms that underlie the susceptibility of developing motor defects in response to exposure to pesticides in a Drosophila model of idiopathic Parkinson’s Disease(iPD)

Background: iPD cases cannot relate to a mendelian inheritance pattern and represent nearly 85% of PD cases. Pesticide exposure that affects mitochondria is a known environmental risk factor for iPD development. The inability to control the environment in human populations makes it difficult to study the role of genotype by environment interaction (GxE) in iPD and to identify genes underlying these effects. The Drosophila rotenone model of iPD has been widely used to study PD-like pathophysiology.

Method: We study the climbing behavior of 117 lines of the Drosophila Genetic Reference Panel (DGRP) exposed to a sublethal rotenone concentration of 250 μM. We partitioned the variance in the DGRP using mixed model ANOVA. We performed GWAS using line means using the DGRP pipeline (http://dgrp2.gnets.ncsu.edu/). We carried out tissue-specific RNAi-mediated knockdown of Mlf using UAS-GAL4 system.

Results: Exposure to a sublethal concentration of rotenone affects climbing and does not affect dopaminergic neuron viability after five days of treatment. DGRP strains exhibit variable climbing behavior in response to rotenone. Genetic variation and GxE contribute 19 and 9% to phenotypic variation, respectively. GxE GWAS identified a strong signal at chromosome 2 mapping to the Mlf gene, the homologous of Mieloyd leukemia factor-1 and 2 (MLF1and MLF2). Constitutive and dopaminergic neuron Mlf knockdown results in lethality in control media and media supplemented with rotenone. Similarly, pan-neuronal expression results in early adult lethality in flies exposed to rotenone, and in control media, few survivors failed to climb.

Conclusion: Our results show that genotype influences the effects of sublethal concentration rotenone in climbing performance. Moreover, it strongly suggests that variation in Mlf expression in neurons underlies the variability in motor behavior effects caused by exposure to rotenone. Since MLF1 associates with PD through HtrA2 regulation at the mitochondria, and iPSCs carrying PINK1 ILE368ASN mutation overexpresses MLF1, we propose that GxE associated with Mlf variation act at the mitochondria in neurons.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/uncovering-the-mechanisms-of-genotype-by-environment-interaction-in-an-idiopathic-parkinsons-disease-model-in-drosophila/