Idiopathic Parkinson's disease (PD) is a debilitating, progressive, neurodegenerative disease. Epidemiological studies have identified age and exposure to metals and other toxicants as risk factors for PD. Oxidative stress and mitochondrial dysfunction are hypothesized to be the basic causes of neuron death in PD. The objective of this research proposal is to define the role of catechol adduction in the genesis of PD. Catechols can undergo transition metal-catalyzed autoxidation to quinones and then be reduced to catechols again in a process termed redox cycling. The redox cycling of catechols to quinones leads to the generation of cytotoxic reactive oxygen species and to the formation of catechol thioether adducts via the addition of a thiol to the quinone. A catechol thioether adduct has a lower oxidation potential and may redox cycle at a faster rate than the parent catechol. The first two specific aims of this research are designed to test whether catechol thioether adducts can generate more reactive oxygen species and adduct proteins at a greater rate than native catechols. This will be accomplished by measuring the oxidation potentials of catechol thioether adducts, the reactive oxygen species generated by these adducts, and the rate of protein adduction by these adducts. The last specific aim of this proposal is to test the effects of catechol adduction upon mitochondrial function. This will be accomplished by studying the effects of catechol adducts upon mitochondrial respiration, specific respiratory complexes, and mitochondrial electron carriers.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32ES005826-03
Application #
6164604
Study Section
Special Emphasis Panel (ZRG4-ALTX-3 (01))
Program Officer
Shreffler, Carol K
Project Start
2000-03-01
Project End
Budget Start
2000-03-01
Budget End
2001-02-28
Support Year
3
Fiscal Year
2000
Total Cost
$40,936
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Pathology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Picklo, M J; Amarnath, V; McIntyre, J O et al. (1999) 4-Hydroxy-2(E)-nonenal inhibits CNS mitochondrial respiration at multiple sites. J Neurochem 72:1617-24