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Environmental Mitochondrial Toxicants Cause LRRK2 Activation in Parkinson's Disease

环境线粒体毒物导致帕金森病中 LRRK2 激活

基本信息

批准号：
10450044
负责人：
Briana De Miranda
金额：
$ 24.9万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10450044
关键词：
Acute Adult Affect Animal Model Antibodies Antigen Presentation Attenuated Autophagocytosis Biological Assay CRISPR/Cas technology Cell Line Cell membrane Cell surface Cells Clustered Regularly Interspaced Short Palindromic Repeats Complex DNA Sequence Alteration Development Disease Dose Embryo Environment Environmental Pollution Environmental Risk Factor Etiology Exposure to Foundations Functional disorder Funding Gene Mutation Genes Genetic Engineering Genetic Predisposition to Disease Genus Hippocampus Goals Herbicides Human Idiopathic Parkinson Disease Immune Impairment Individual Industrialization Inherited Ketoglutarate Dehydrogenase Complex LRRK2 gene Lead Ligation Link Measures Mentors Mentorship Mitochondria Mitochondrial Proteins Modeling Movement Disorders Mutation Nerve Degeneration Neurons PARK8 gene Paraquat Parkinson Disease Pathogenesis Pathogenicity Pathologic Pathology Penetrance Pesticides Phase Phosphorylation Phosphotransferases Population Positioning Attribute Proteins Rattus Reporting Research Risk Risk Factors Rodent Model Role Rotenone Soil Solvents Susceptibility Gene Technology Therapeutic Toxic Environmental Substances Toxic effect Toxicant exposure Toxicology Training Trichloroethylene Vesicle aged alpha synuclein base cellular pathology combat cytotoxic disorder risk dopaminergic neuron drinking water gene environment interaction ground water in vivo inhibitor innovation kidney cell kinase inhibitor mitochondrial dysfunction mutant neuroinflammation neuron loss nigrostriatal degeneration novel novel therapeutics organic contaminant programs protein transport response targeted treatment tenure track toxicant trafficking

项目摘要

Abstract The cause of idiopathic Parkinson’s disease (PD) remains unknown, however, significant evidence suggests that interaction between genetic susceptibility and environmental factors is the predominant etiology of PD. Environmental toxicants that cause mitochondrial dysfunction, such as the organic pesticide rotenone, and the common herbicide paraquat, are associated with elevated PD risk (OR 2.5, 95% CI: 0.1.3-4.7; OR 2.5, 95% CI: 1.4-4.7; respectively). A heavily used industrial solvent, trichloroethylene (TCE), also causes mitochondrial toxicity, and is the most frequently reported organic contaminant found in US groundwater. TCE exposure is linked to the development of PD (OR 6.1, 95% CI: 1.2-3.3), and rodent models of TCE exposure display dopamine neuron degeneration from the nigrostriatal tract. Recent evidence from our lab indicates that rotenone (ROT), paraquat (PQ), and TCE interact with PD susceptibility genes, notably, causing the activation of LRRK2 in wildtype (WT) human embryonic kidney (HEK) cells, which could be blocked by a selective LRRK2 inhibitor (GNE-7915). As LRRK2 is the most commonly inherited mutation associated with familial PD, this evidence suggests that a gene-environment interaction exists between LRRK2 and mitochondrial toxicants. Functionally, LRRK2 activation leads to multiple downstream cellular pathologies, such as disruption of vesicular trafficking, deficits in autophagy, the phosphorylation of α-synuclein, and neuroinflammation; all of which are mechanisms hypothesized to precede dopamine neuron degeneration in PD. The basis of this proposal is to investigate LRRK2 activation and pre-degenerative mechanisms in dopamine neurons caused by environmental mitochondrial toxicants. To achieve this, we will pursue the following specific aims: Aim 1 (K99) will build a foundation to identify if LRRK2 activity is induced in WT neurons by environmental mitochondrial toxicants, and if LRRK2 mutations exacerbate this pathology following mitochondrial dysfunction. Aim 2 (R00) will further characterize LRRK2 activation in an animal model of TCE exposure, and determine whether LRRK2 inhibition is protective against TCE. Aim 3 (R00) will characterize another pre-degenerative mechanism influenced by environment mitochondrial toxicants and LRRK2, mitochondrial antigen presentation (MitAP). MitAP involves the trafficking of mitochondrial proteins from the inner lumen to cell surface MHC molecules, causing the selective killing of dopamine neurons by immune cells. We have measured MitAP in dopamine neurons following a single exposure to ROT in rats, suggesting this is an early response to mitochondrial toxicity. We will identify whether ROT, PQ, and TCE induce MitAP in dopaminergic neurons. As LRRK2 activity affects vesicular trafficking, we propose that LRRK2 mutations in N27 cell lines influences MitAP in response to mitochondrial toxicant exposure, and treatment with a LRRK2 inhibitor may be protective against MitAP in vivo. These aims will provide innovative evidence for LRRK2 activation by environmental factors that contributes to dopaminergic neuron degeneration. Collectively, this proposal may lead to new therapeutic treatment avenues for idiopathic and inherited PD.

摘要

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Rest and Digest-The Basal Role of Autophagy in Neurons and Its Relevance to Parkinson's Disease.

DOI：
10.1002/mds.29165
发表时间：
2022-09
期刊：
Movement disorders : official journal of the Movement Disorder Society
影响因子：
0
作者：
通讯作者：

Trichloroethylene: An Invisible Cause of Parkinson's Disease?

DOI：
10.3233/jpd-225047
发表时间：
2023
期刊：
Journal of Parkinson's disease
影响因子：
0
作者：
Dorsey ER;Zafar M;Lettenberger SE;Pawlik ME;Kinel D;Frissen M;Schneider RB;Kieburtz K;Tanner CM;De Miranda BR;Goldman SM;Bloem BR
通讯作者：
Bloem BR

Oral ingestion of the environmental toxicant trichloroethylene in rats induces alterations in the gut microbiome: Relevance to idiopathic Parkinson's disease.