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 #
5R01ES017540-02
Application #
8320863
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
2012-05-01
Budget End
2013-04-30
Support Year
2
Fiscal Year
2012
Total Cost
$385,845
Indirect Cost
$137,261
Name
Duke University
Department
None
Type
Schools of Earth Sciences/Natur
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Rooney, J P; Luz, A L; González-Hunt, C P et al. (2014) Effects of 5'-fluoro-2-deoxyuridine on mitochondrial biology in Caenorhabditis elegans. Exp Gerontol 56:69-76
Meyer, Joel N; Leung, Maxwell C K; Rooney, John P et al. (2013) Mitochondria as a target of environmental toxicants. Toxicol Sci 134:1-17
Leung, Maxwell C K; Rooney, John P; Ryde, Ian T et al. (2013) Effects of early life exposure to ultraviolet C radiation on mitochondrial DNA content, transcription, ATP production, and oxygen consumption in developing Caenorhabditis elegans. BMC Pharmacol Toxicol 14:9
Bess, Amanda S; Ryde, Ian T; Hinton, David E et al. (2013) UVC-induced mitochondrial degradation via autophagy correlates with mtDNA damage removal in primary human fibroblasts. J Biochem Mol Toxicol 27:28-41