Parkinson's disease (PD) involves pathological loss of neurons. The long-term objective of this research in our laboratory is to understand how environmental and genetic neurotoxic agents interact to signal and regulate the survival/apoptosis machinery in PD pathogenesis. Mitochondrial dysfunction has been propsoed as a key mechanism that mediates demise of dopamingergic neurons in PD. However, the detailed molecular mechanisms by which PD relevant environmental toxicants affect mitochondria! transcription and activity remain unknown. Our recently published findings highlight the key role.of nuclear transcription factor myocyte enhancer factor 2 (MEF2) in neuronal survival. Our unpublished studies have revealed unexpected presence and function of MEF2 in mitochondria. Based on this, we propose to explore the role of mitochondrial MEF2 in mediating and integrating the toxic signals of PD relevant environmental toxicants in the degeneration of dopamine neurons. We propose to: I. Determine the role of mitochondrial MEF2 in regulating transcription of mitochondrial genome in dopaminergic neurons;II. Study the regulation of mitochondrial MEF2 by PD relevant environmental toxicants in mitochondrial dysfunction and neuronal death in cellular models;and III. Establish the regulation and function of mitochondrial MEF2 in toxicant-induced animal models of PD. To accomplish aim l-lll, we will establish the role of MEF2 in mitochondrial gene transcription in dopaminergic neuronal cell line SN4741 cells and primary neurons and test a group of model toxicants including MPP+(metabolite of MPTP) and rotenone in cellular and rodent modeis to investigate whether de-regulation of mitochondrial MEF2 mediates the toxic effects of these toxins. We will attempt to extend our findings to PD patients by correlating the levels and activit of mitochondrial MEF2 with the disease. We will use a combination of morphological, biochemical, functional and genetic methods in the proposed study. These studies will allow us to assess whether targeting mitochondrial MEF2 underlies environmental toxicant-induced apoptosis of dopamine neurons. The novel insight gained from this study will demonstrate how environmental toxicants may disrupt mitochondrial function, providing a molecular explanation for the loss of dopamine neurons that may relevant to both sporadic and familial PD and a potential therapeutic target.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Program Projects (P01)
Project #
5P01ES016731-05
Application #
8376979
Study Section
Special Emphasis Panel (ZES1-LWJ-G)
Project Start
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
5
Fiscal Year
2012
Total Cost
$326,977
Indirect Cost
$114,103
Name
Emory University
Department
Type
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Lohr, Kelly M; Masoud, Shababa T; Salahpour, Ali et al. (2017) Membrane transporters as mediators of synaptic dopamine dynamics: implications for disease. Eur J Neurosci 45:20-33
Qi, Zhen; Voit, Eberhard O (2017) Inference of cancer mechanisms through computational systems analysis. Mol Biosyst 13:489-497
Frediani, Jennifer K; Sanikidze, Ekaterina; Kipiani, Maia et al. (2016) Macronutrient intake and body composition changes during anti-tuberculosis therapy in adults. Clin Nutr 35:205-12
Jones, Dean P (2016) Sequencing the exposome: A call to action. Toxicol Rep 3:29-45
Qi, Zhen; Yu, Gina P; Tretter, Felix et al. (2016) A heuristic model for working memory deficit in schizophrenia. Biochim Biophys Acta 1860:2696-705
Panuwet, Parinya; Hunter Jr, Ronald E; D'Souza, Priya E et al. (2016) Biological Matrix Effects in Quantitative Tandem Mass Spectrometry-Based Analytical Methods: Advancing Biomonitoring. Crit Rev Anal Chem 46:93-105
Kannarkat, G T; Cook, D A; Lee, J-K et al. (2015) Common Genetic Variant Association with Altered HLA Expression, Synergy with Pyrethroid Exposure, and Risk for Parkinson's Disease: An Observational and Case-Control Study. NPJ Parkinsons Dis 1:
Qi, Zhen; Tretter, Felix; Voit, Eberhard O (2014) A heuristic model of alcohol dependence. PLoS One 9:e92221
Taylor, Tonya N; Alter, Shawn P; Wang, Minzheng et al. (2014) Reduced vesicular storage of catecholamines causes progressive degeneration in the locus ceruleus. Neuropharmacology 76 Pt A:97-105
Qi, Zhen; Voit, Eberhard O (2014) Identification of cancer mechanisms through computational systems modeling. Transl Cancer Res 3:233-242

Showing the most recent 10 out of 85 publications