The long-range goal of this research is to elucidate the role of persistent mitochondrial DNA damage in neurodegeneration. There is now strong evidence that neurodegeneration in the majority of Parkinson's Disease cases is the result of the interplay of genetic differences with environmental exposures (gene-environment interactions), but neither the genes nor the environmental exposures involved are well understood. We are investigating the novel hypothesis that some important environmental toxins contribute to neurodegeneration by causing persistent mitochondrial DNA damage, and that genetic deficiencies in the processes that handle such damage lead to greater susceptibility. Mitochondrial DNA is more sensitive than nuclear DNA to many insults, and there is no apparent repair pathway for handling mitochondrial DNA damage caused by important environmental genotoxins such as polycyclic aromatic hydrocarbons and ultraviolet radiation. We will test the role of such damage in causing neurodegeneration as a result of exposure during key developmental time periods. The specificity of this effect will be tested using innovative new transgenic strains of Caenorhabditis elegans. We will also test the hypothesis that specific genes involved in mitochondrial fusion and autophagy protect against such damage, taking advantage of the genetic and molecular tools available in Caenorhabditis elegans. Description of relevance to public health There is now strong evidence that neurodegeneration in most Parkinson's Disease cases is the result of the combined effects of genetic differences and environmental exposures (gene- environment interactions), but neither the genes nor the environmental exposures involved are well understood. We will test the hypothesis that important, common environmental toxins contribute to neurodegeneration act by causing persistent mitochondrial DNA damage during vulnerable periods of development, and that genetic deficiencies in the processes that handle such damage lead to greater susceptibility. If this is the case, better regulation of such chemicals could greatly reduce the incidence of Parkinson's Disease, and possibly other neurodegenerative diseases as well.

Public Health Relevance

There is now strong evidence that neurodegeneration in most Parkinson's Disease cases is the result of the combined effects of genetic differences and environmental exposures (gene- environment interactions), but neither the genes nor the environmental exposures involved are well understood. We will test the hypothesis that important, common environmental toxins contribute to neurodegeneration act by causing persistent mitochondrial DNA damage during vulnerable periods of development, and that genetic deficiencies in the processes that handle such damage lead to greater susceptibility. If this is the case, better regulation of such chemicals could greatly reduce the incidence of Parkinson's Disease, and possibly other neurodegenerative diseases as well.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES017540-03
Application #
8463182
Study Section
Special Emphasis Panel (ZES1-TN-J (R0))
Program Officer
Lawler, Cindy P
Project Start
2011-08-16
Project End
2016-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
3
Fiscal Year
2013
Total Cost
$353,961
Indirect Cost
$125,734
Name
Duke University
Department
Type
Schools of Earth Sciences/Natur
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Meyer, Joel N; Leuthner, Tess C; Luz, Anthony L (2017) Mitochondrial fusion, fission, and mitochondrial toxicity. Toxicology 391:42-53
Luz, Anthony L; Godebo, Tewodros R; Smith, Latasha L et al. (2017) Deficiencies in mitochondrial dynamics sensitize Caenorhabditis elegans to arsenite and other mitochondrial toxicants by reducing mitochondrial adaptability. Toxicology 387:81-94
Wyatt, Lauren H; Luz, Anthony L; Cao, Xiou et al. (2017) Effects of methyl and inorganic mercury exposure on genome homeostasis and mitochondrial function in Caenorhabditis elegans. DNA Repair (Amst) 52:31-48
Meyer, Joel N; Chan, Sherine S L (2017) Sources, mechanisms, and consequences of chemical-induced mitochondrial toxicity. Toxicology 391:2-4
Hartman, Jessica H; Miller, Grover P; Meyer, Joel N (2017) Toxicological Implications of Mitochondrial Localization of CYP2E1. Toxicol Res (Camb) 6:273-289
Van Houten, Bennett; Hunter, Senyene E; Meyer, Joel N (2016) Mitochondrial DNA damage induced autophagy, cell death, and disease. Front Biosci (Landmark Ed) 21:42-54
Gonzalez-Hunt, Claudia P; Rooney, John P; Ryde, Ian T et al. (2016) PCR-Based Analysis of Mitochondrial DNA Copy Number, Mitochondrial DNA Damage, and Nuclear DNA Damage. Curr Protoc Toxicol 67:20.11.1-20.11.25
Luz, Anthony L; Godebo, Tewodros R; Bhatt, Dhaval P et al. (2016) From the Cover: Arsenite Uncouples Mitochondrial Respiration and Induces a Warburg-like Effect in Caenorhabditis elegans. Toxicol Sci 152:349-62
Luz, Anthony L; Meyer, Joel N (2016) Effects of reduced mitochondrial DNA content on secondary mitochondrial toxicant exposure in Caenorhabditis elegans. Mitochondrion 30:255-64
Luz, Anthony L; Lagido, Cristina; Hirschey, Matthew D et al. (2016) In Vivo Determination of Mitochondrial Function Using Luciferase-Expressing Caenorhabditis elegans: Contribution of Oxidative Phosphorylation, Glycolysis, and Fatty Acid Oxidation to Toxicant-Induced Dysfunction. Curr Protoc Toxicol 69:25.8.1-25.8.22

Showing the most recent 10 out of 27 publications