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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
NIH Challenge Grants and Partnerships Program (RC1)
Project #
1RC1ES018058-01
Application #
7810140
Study Section
Special Emphasis Panel (ZRG1-BDCN-T (58))
Program Officer
Lawler, Cindy P
Project Start
2009-09-21
Project End
2011-06-30
Budget Start
2009-09-21
Budget End
2010-06-30
Support Year
1
Fiscal Year
2009
Total Cost
$500,000
Indirect Cost
Name
University of Pittsburgh
Department
Neurology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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Tapias, Victor; Cannon, Jason R; Greenamyre, J Timothy (2014) Pomegranate juice exacerbates oxidative stress and nigrostriatal degeneration in Parkinson's disease. Neurobiol Aging 35:1162-76
Tapias, Victor; Greenamyre, J Timothy (2014) A rapid and sensitive automated image-based approach for in vitro and in vivo characterization of cell morphology and quantification of cell number and neurite architecture. Curr Protoc Cytom 68:12.33.1-22
Tapias, Victor; Greenamyre, J Timothy; Watkins, Simon C (2013) Automated imaging system for fast quantitation of neurons, cell morphology and neurite morphometry in vivo and in vitro. Neurobiol Dis 54:158-68
Cannon, Jason R; Geghman, Kindiya D; Tapias, Victor et al. (2013) Expression of human E46K-mutated *-synuclein in BAC-transgenic rats replicates early-stage Parkinson's disease features and enhances vulnerability to mitochondrial impairment. Exp Neurol 240:44-56
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