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Environmental toxin interactions with genetic risks for Parkinson's disease

环境毒素与帕金森病遗传风险的相互作用

基本信息

批准号：
8232880
负责人：
David Evan Krantz
金额：
$ 15万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-01 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8232880
关键词：
Affect Age Animal Model Attention Cessation of life Contracts Data Disease Dopamine Dopaminergic Cell Drosophila genus Drosophila melanogaster Environment Environmental Risk Factor Future Genes Genetic Genetic Models Genetic Risk Homeostasis Homologous Gene Human Link Mitochondria Modeling Mutation Nerve Degeneration Onset of illness Organism Paraquat Parkinson Disease Pathway interactions Pesticides Phenotype Play Process Proteins Relative (related person)Risk Risk Factors Role Rotenone Synaptic Vesicles Testing Time Toxic Environmental Substances Toxic effect Toxin Ubiquitination Work diphenyl disorder risk dopaminergic neuron environmental agent fly gene environment interaction interest killings member mitochondrial dysfunction mutant neurotoxic parkin gene/protein research study synergism ubiquitin ligase vesicular monoamine transporter

项目摘要

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：基因和环境毒素都可能是帕金森病（PD）的危险因素，但它们之间潜在的相互作用仍然知之甚少。该建议旨在研究基因-环境相互作用，可能与PD使用的模式生物果蝇。人们的注意力将集中在与PD相关的基因和毒素上，这些基因和毒素影响线粒体功能障碍、蛋白质遍在化和多巴胺稳态。果蝇囊泡单胺转运蛋白（DVMAT）的过表达已被证明可以防止至少一种与PD相关的突变基因（parkin）和至少一种选择性杀死多巴胺能神经元的杀虫剂（鱼藤酮）的神经毒性作用。因此，本研究将测试的假设，即VMAT的神经保护作用将扩展到不同的毒素，百草枯，认为通过不同的机制比鱼藤酮，这是否需要其本地化的突触囊泡，如果它是需要在一个特定的时间相对于神经毒性的侮辱。这里的研究表明，突变形式的parkin的过度表达会导致果蝇多巴胺能细胞变性。如果parkin突变作为PD的风险因素，那么额外的环境因素可能会增加这种风险。本研究将使用鱼藤酮、百草枯和其他药剂来检验这一假设。将使用PD相关基因pink 1进行基因-环境相互作用的平行实验。最后，已经建立的粉红色突变表型将用于筛选拯救线粒体功能障碍的神经毒性作用的药物。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Moving beyond energy homeostasis: new roles for glucagon-like peptide-1 in food and drug reward.

DOI：
10.1016/j.neuint.2013.10.003
发表时间：
2014-07
期刊：
Neurochemistry international
影响因子：
4.2
作者：
Reddy IA;Stanwood GD;Galli A
通讯作者：
Galli A

The Drosophila vesicular monoamine transporter reduces pesticide-induced loss of dopaminergic neurons.

DOI：
10.1016/j.nbd.2010.05.008
发表时间：
2010-10
期刊：
Neurobiology of disease
影响因子：
6.1
作者：
Lawal HO;Chang HY;Terrell AN;Brooks ES;Pulido D;Simon AF;Krantz DE
通讯作者：
Krantz DE

A glial variant of the vesicular monoamine transporter is required to store histamine in the Drosophila visual system.

DOI：
10.1371/journal.pgen.1000245
发表时间：
2008-11
期刊：
PLoS genetics
影响因子：
4.5
作者：
Romero-Calderón R;Uhlenbrock G;Borycz J;Simon AF;Grygoruk A;Yee SK;Shyer A;Ackerson LC;Maidment NT;Meinertzhagen IA;Hovemann BT;Krantz DE
通讯作者：
Krantz DE