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.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZES1-LWJ-E (CG))
Program Officer
Mcallister, Kimberly A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Los Angeles
Schools of Medicine
Los Angeles
United States
Zip Code
Aguilar, Jenny I; Dunn, Matthew; Mingote, Susana et al. (2017) Neuronal Depolarization Drives Increased Dopamine Synaptic Vesicle Loading via VGLUT. Neuron 95:1074-1088.e7
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
Freyberg, Zachary; Sonders, Mark S; Aguilar, Jenny I et al. (2016) Mechanisms of amphetamine action illuminated through optical monitoring of dopamine synaptic vesicles in Drosophila brain. Nat Commun 7:10652
Lawal, H O; Terrell, A; Lam, H A et al. (2014) Drosophila modifier screens to identify novel neuropsychiatric drugs including aminergic agents for the possible treatment of Parkinson's disease and depression. Mol Psychiatry 19:235-42
Reddy, India A; Stanwood, Gregg D; Galli, Aurelio (2014) Moving beyond energy homeostasis: new roles for glucagon-like peptide-1 in food and drug reward. Neurochem Int 73:49-55
Martin, Ciara A; Krantz, David E (2014) Drosophila melanogaster as a genetic model system to study neurotransmitter transporters. Neurochem Int 73:71-88
Martin, Ciara A; Barajas, Angel; Lawless, George et al. (2014) Synergistic effects on dopamine cell death in a Drosophila model of chronic toxin exposure. Neurotoxicology 44:344-51
Grygoruk, Anna; Chen, Audrey; Martin, Ciara A et al. (2014) The redistribution of Drosophila vesicular monoamine transporter mutants from synaptic vesicles to large dense-core vesicles impairs amine-dependent behaviors. J Neurosci 34:6924-37
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

Showing the most recent 10 out of 16 publications