Both genes and environmental toxins may act as risk factors for Parkinson's disease (PD), but their potential interplay remains poorly understood. This proposal seeks to investigate gene-environment interactions that are potentially relevant to PD using the model organism Drosophila melanogaster. Attention will be directed on genes and toxins associated with PD that affect mitochondrial dysfunction, protein ubiquitination and dopamine homeostasis. Over-expression of the Drosophila vesicular monoamine transporter (DVMAT) has been shown to protect against the neurotoxic effects of at least one mutant gene associated with PD (parkin), and at least one pesticide (rotenone) that selectively kills dopaminergic neurons. This study will therefore test the hypothesis that the neuroprotective effects of VMAT will extend to a different toxin, paraquat, thought to act by a different mechanism than rotenone, and whether this requires its localization to synaptic vesicles and if it is required at a specific time relative to neurotoxic insults. Studies here have shown that over-expression of mutant forms of parkin can cause dopaminergic cell degeneration in flies. If mutations in parkin function as a risk factor for PD, then additional environmental agents may enhance this risk. This study will test this hypothesis using rotenone, paraquat and other agents. Parallel experiments for gene-environment interactions will be performed with the PD related gene, pink1. Finally, already established pink mutant phenotypes will be used to screen for agents that rescue the neurotoxic effects of mitochondrial dysfunction.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
3R01ES015747-04S1
Application #
8232880
Study Section
Special Emphasis Panel (ZES1-LWJ-E (CG))
Program Officer
Mcallister, Kimberly A
Project Start
2007-08-01
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2012-05-31
Support Year
4
Fiscal Year
2011
Total Cost
$149,999
Indirect Cost
Name
University of California Los Angeles
Department
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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Martin, Ciara A; Myers, Katherine M; Chen, Audrey et al. (2016) Ziram, a pesticide associated with increased risk for Parkinson's disease, differentially affects the presynaptic function of aminergic and glutamatergic nerve terminals at the Drosophila neuromuscular junction. Exp Neurol 275 Pt 1:232-41
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Lawal, Hakeem O; Krantz, David E (2013) SLC18: Vesicular neurotransmitter transporters for monoamines and acetylcholine. Mol Aspects Med 34:360-72
Chen, Audrey; Ng, Fanny; Lebestky, Tim et al. (2013) Dispensable, redundant, complementary, and cooperative roles of dopamine, octopamine, and serotonin in Drosophila melanogaster. Genetics 193:159-76

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