Gene-environment interactions in transgenic rat models of Parkinson disease

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DESCRIPTION (provided by applicant): (See instructions): General Challenge Area 15: Translational Science. Challenge Topic 15-ES-101: Effects of Environmental Exposures on Phenotypic Outcomes Using Non-Human Models. Monogenic forms of Parkinson disease (PD) are uncommon, accounting for about 10% of all cases - and purely environmental causes of parkinsonism are rare. The vast majority of PD is believed to result from a lifetime of environmental exposures superimposed on genetic susceptibility, but the nature of these gene- environment interactions is unclear. We will examine the effects of a clinically relevant pesticide, rotenone, on phenotypic outcomes in transgenic rat models of PD. While rotenone has been used to model features of PD in rats, only now is there epidemiological evidence indicating that rotenone is a bona fide risk factor for human PD. The rotenone model of PD has been limited by its variability, but we have overcome this barrier by creating a new highly reproducible model. Unfortunately, the rotenone model does not work well in mice, so it has been impossible to use genetically modified (transgenic; Tg) mice to examine gene- environment interactions with this pesticide. Although there are many Tg mouse models of PD, they have provided somewhat limited insights into pathogenesis, and generally do not reproduce key behavioral or pathological features of the human disease. Moreover, conventional Tg mice are limited technically by positional effects of the transgene insertion site, by limited transgene size/structure, and by use of 'artificial' promoters. To overcome this barrier, we have created BAC Tg rats that are insulated from positional effects of insertion site, and which can be regulated by their native promoters. Specifically, we have created Tg rats that overexpress WT and mutant human alpha-synuclein (AS) and mutant LRRK2. Increased expression of WT AS from gene dupli- & triplications causes PD, and promoter polymorphisms that increase AS expression may be associated with increased risk of developing 'sporadic' or 'idiopathic' PD. LRRK2 mutations are the most common cause of autosomal dominant PD. In some populations, up to 40% of individuals carry LRRK2 mutations, but penetrance is highly variable. As such, some LRRK2 mutations may be risk factors for PD rather than causative per se - and environmental exposures may play a major role in disease expression. With the development of these new rat models, we can now study rotenone effects in Tg animals. This project represents a collaboration between the Greenamyre lab (rotenone model) and the Chenjian Li lab (Tg rat models) to study the effects of a known environmental risk factor on the phenotype of novel genetic models of PD using a variety of relevant behavioral, pathological and biochemical outcomes. PUBLIC HEALTH RELEVANCE: The vast majority of PD is believed to result from a lifetime of environmental exposures superimposed on an individual's composite genetic susceptibility, but the nature of these gene-environment interactions is unclear. This project will examine the effects of a clinically relevant pesticide, rotenone, on phenotypic outcomes in transgenic rat models of PD. As such, we will begin to define the relationship between a known environmental risk factor and identified genetic risk factors in the causation of this devastating illness.