Quantifiable Gene-Environment Interactions and the Risk for Parkinson s Disease Following Neurotoxin Exposure
Abstract
Considerable progress has been made over the last few decades in identifying individual genetic and environmental risk factors that can contribute to a person s risk of developing Parkinson s disease (PD). Human studies have taught us that certain pesticides are neurotoxins and that chronic dietary, residential, occupational, or combat exposure to these can increase the risk of developing PD. Yet, it is becoming increasingly clear that PD in any individual person is not just due to their environmental exposures or just due to their genetic makeup, but a complex relationship between these two factors, or so-called gene - environment interactions. As a result, not every person chronically exposed to the pesticide maneb will develop PD, just as not every person who carries a familial PD mutation in the LRRK2 gene will do so either. With this insight, it becomes apparent that finding genetic and environmental risk factors could ultimately be leveraged to combat disease onset and progression through new therapeutic approaches. In human studies, it is extremely challenging to identify the specific genetic risk factors that add weight to or counterbalance PD risk following pesticide exposures. This is where the power of animal models comes to the fore. By combining advanced genetic approaches with rigorously controlled environmental exposures, we can use animal studies to identify specific genetic risk factors underlying neurodegeneration caused by pesticides. Rapid advances in animal studies will, in turn, enable us to make informed choices about what molecules to target when designing therapies for the clinic. Perhaps surprisingly, some of the clearest insights into what goes awry genetically in PD have come from research using the common fruit fly Drosophila melanogaster. This is because (i) many features of human nervous system function and genetic makeup are shared with flies, (ii) Drosophila have dopamine-producing neurons that control movement as they do in humans, (iii) flies only live for about 2 months, yet they display many hallmarks of nervous system aging seen in humans over this short period. Most importantly, there are sophisticated tools to manipulate flies genetically, which distinguishes them for the study of gene - environment interactions, our focus area here. We will use a powerful research pipeline consisting of (i) Drosophila genetic studies to discover genes that influence pesticide-induced neurodegeneration and (ii) biological validation of genes identified from fly studies in mouse models. We will address several major challenges to the field: First, we will perform a comprehensive search to identify genes that, when functionally altered, can modulate the loss of dopamine neurons in flies exposed to the pesticide maneb. Maneb is widely used throughout the U.S. and epidemiological studies link its exposure to elevated PD risk. Despite this, very little is known about how maneb damages dopamine neurons, hence there is considerable untapped potential for gaining new insight into PD neurodegeneration. We have developed a Drosophila model that harnesses gene - environment interactions to enable the identification of genes associated with maneb-induced dopamine neuron loss. Second, we will perform a parallel search for genes that alter the loss of dopamine neurons in flies exposed to low-dose paraquat. Maneb and paraquat are used agriculturally with geographical overlap and are thought to act synergistically in damaging dopamine neurons. We will compare genes arising from these two parallel searches so that we can confidently assess whether maneb and paraquat have shared or unique mechanisms that drive neuronal death, how these mechanisms could fit together, and what this teaches us about PD development. Third, we will evaluate candidate genes from fly studies in mouse models of maneb- or paraquat-induced neurodegeneration. This will generate a set of validated genes that illuminate
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110703
Entities
People
- Ian Martin
Organizations
- Oregon Health & Science University
- United States Army