The long-term goal of this proposal is to determine the mechanisms by which environmental agents produce neurodegeneration. Environmental neurotoxicants are strongly implicated in the etiology of neurodegenerative diseases such as Parkinson's disease (PD). Redox cycling agents such as the herbicide paraquat (PQ2+) are found in the environment and several compounds in this class have come under investigation as neurotoxic agents based on the ability to produce reactive oxygen species (ROS) in an aerobic environment and epidemiological reports linking their exposure with increased risk of PD. However, the cellular and molecular mechanisms by which environmental redox cycling agents produce ROS and resultant neurotoxicity remain incompletely understood. It is hypothesized that the mitochondria play a key role in ROS production by redox cycling agents and consequent neurotoxicity. The hypothesis predicts that redox cycling agents such as PQ2+ increase mitochondrial ROS production by a mechanism involving its partial reduction by electrons of the electron transport chain to form the PQ+. radical via complex III as the redox enzyme. The hypothesis further predicts that mitochondria are a target of redox cycling agents and scavenging mitochondrial oxidants will ameliorate neurotoxicity. To address this, the following specific aims are proposed.
Specific Aim 1 : Determine the mitochondrial mechanism of ROS generation and neurotoxicity by redox cycling agents.
Specific Aim 2 : Determine if mitochondria are a source and a target of oxidative stress produced by redox cycling agents in dopaminergic cells in vivo.
Specific Aim 3 : Determine if mitochondrially targeted therapies ameliorate mitochondrial oxidative stress and neurotoxicity produced by in vivo administration of redox cycling agents. These studies can elucidate the mechanism by which exposure to environmental redox cycling agents can injure dopaminergic neurons and provide a rational therapy to treat neurotoxicant-induced Parkinson's disease.

Public Health Relevance

A steadily growing body of literature suggests that environmental agents alone, or in combination with genetic factors or other toxicants may predispose individuals to neurodegenerative diseases such as Parkinson's disease (PD). Paraquat and diquat are widely used prototypical redox cycling environmental agents with the potential of causing parkinsonism. The extensive use of these agents as a landscape and aquatic herbicides underscores the importance of their environmental and occupational risk. Therefore, elucidating the molecular mechanisms of such agents and development of rational therapeutic strategies that penetrate the blood brain barrier is critical.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS045748-09
Application #
8385547
Study Section
Special Emphasis Panel (ZRG1-BDCN-J (03))
Program Officer
Sieber, Beth-Anne
Project Start
2003-04-01
Project End
2014-11-30
Budget Start
2012-12-01
Budget End
2014-11-30
Support Year
9
Fiscal Year
2013
Total Cost
$260,335
Indirect Cost
$74,150
Name
University of Colorado Denver
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Lopert, Pamela; Patel, Manisha (2014) Brain mitochondria from DJ-1 knockout mice show increased respiration-dependent hydrogen peroxide consumption. Redox Biol 2:667-72
Liang, Li-Ping; Kavanagh, Terrance J; Patel, Manisha (2013) Glutathione deficiency in Gclm null mice results in complex I inhibition and dopamine depletion following paraquat administration. Toxicol Sci 134:366-73
Durazo, Shelley A; Kadam, Rajendra S; Drechsel, Derek et al. (2011) Brain mitochondrial drug delivery: influence of drug physicochemical properties. Pharm Res 28:2833-47
Good, Renee L; Liang, Li-Ping; Patel, Manisha et al. (2011) Mouse strain- and age-dependent effects of binge methamphetamine on dopaminergic signaling. Neurotoxicology 32:751-9
Cantu, David; Fulton, Ruth E; Drechsel, Derek A et al. (2011) Mitochondrial aconitase knockdown attenuates paraquat-induced dopaminergic cell death via decreased cellular metabolism and release of iron and H?O?. J Neurochem 118:79-92
Drechsel, Derek A; Patel, Manisha (2010) Respiration-dependent H2O2 removal in brain mitochondria via the thioredoxin/peroxiredoxin system. J Biol Chem 285:27850-8
Hoschouer, Emily L; Finseth, Taylor; Flinn, Sharon et al. (2010) Sensory stimulation prior to spinal cord injury induces post-injury dysesthesia in mice. J Neurotrauma 27:777-87
White, Robin E; McTigue, Dana M; Jakeman, Lyn B (2010) Regional heterogeneity in astrocyte responses following contusive spinal cord injury in mice. J Comp Neurol 518:1370-90
Chick, Wallace S; Drechsel, Derek A; Hammond, Warren et al. (2009) Transmission of mutant phenotypes from ES cells to adult mice. Mamm Genome 20:734-40
Drechsel, Derek A; Patel, Manisha (2009) Differential contribution of the mitochondrial respiratory chain complexes to reactive oxygen species production by redox cycling agents implicated in parkinsonism. Toxicol Sci 112:427-34

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