The etiology of Parkinson's disease (PD) involves gene/environment interaction. While most of the identified genetic mutations affect the ubiquitin-proteasome system (UPS), epidemiological studies and clinical case reports have strongly suggested the association between pesticide exposure and increased incidence of PD. In animal models, selective toxicities to the nigrostriatal dopaminergic neurons occur after systemic exposure to rotenone and paraquat. Oxidative stress is a common mediator of pesticide-induced neurotoxicity. It contributes to PD-related pathological changes such as formation of a-synuclein aggregates and inhibition of proteasomal function. However, the molecular targets of oxidative damage have not been clearly defined and the mechanistic link between mitochondria! and proteasomal dysfunction remains to be determined. In our preliminary studies, we have shown that mitochondrial thioredoxin (mtTrx; Trx2) is particularly susceptible to oxidation induced by a variety of environmental toxicants, including peroxides, rotenone, MPP+ and paraquat. Submicromolar concentrations of rotenone induced persistent oxidation of mtTrx and redistribution of mtTrx to the cytoplasm. Chronic exposure to nanomolar concentrations of rotenone resulted in decreased mtTrx protein. Overexpression of mtTrx protected cells from oxidant-induced apoptosis and inhibited a-synuclein aggregation caused by chronic rotenone toxicity. Downregulation of the mitochondrial thioredoxin reductase (TrxR 2) led to decreased mature mtTrx while increased its precursor form. Furthermore, we identified that mtTrx interacted with mitochondrial heat shock protein 60 which is a key component of the mitochondrial protein processing machinery. Based on these findings, we hypothesize that selective targeting of mtTrx by pesticides and the ensuring oxidation of mtTrx lead to impaired mitochondrial protein import. The hypothesis will be tested with two specific aims.
Specific aim 1 is to determine whether the redox status and expression level of mtTrx control the sensitivity to pesticide-induced toxicity in cultured neuronal cells.
Specific aim 2 is to determine whether the pesticide-induced oxidation inhibits the import of mtTrx and other nuclear DMA-encoded mitochondrial proteins. Results from these studies will define novel protein targets of oxidative injury and will facilitate our understanding towards the molecular mechanisms of environmental toxicities associated with PD. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21ES014668-01A1
Application #
7199443
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Lawler, Cindy P
Project Start
2006-12-01
Project End
2008-11-30
Budget Start
2006-12-01
Budget End
2007-11-30
Support Year
1
Fiscal Year
2007
Total Cost
$215,186
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Stankowski, Jeannette N; Zeiger, Stephanie L H; Cohen, Evan L et al. (2011) C-terminus of heat shock cognate 70 interacting protein increases following stroke and impairs survival against acute oxidative stress. Antioxid Redox Signal 14:1787-801
Ni, Mingwei; Li, Xin; Yin, Zhaobao et al. (2010) Methylmercury induces acute oxidative stress, altering Nrf2 protein level in primary microglial cells. Toxicol Sci 116:590-603
Wang, Ling; Jiang, Haiyan; Yin, Zhaobao et al. (2009) Methylmercury toxicity and Nrf2-dependent detoxification in astrocytes. Toxicol Sci 107:135-43
Chen, Jianbin; Wang, Ling; Chen, Yan et al. (2009) Phosphatidylinositol 3 kinase pathway and 4-hydroxy-2-nonenal-induced oxidative injury in the RPE. Invest Ophthalmol Vis Sci 50:936-42
Chen, Yan; Go, Young-Mi; Pohl, Jan et al. (2008) Increased mitochondrial thioredoxin 2 potentiates N-ethylmaleimide-induced cytotoxicity. Chem Res Toxicol 21:1205-10
Wang, Ling; Chen, Yan; Sternberg, Paul et al. (2008) Essential roles of the PI3 kinase/Akt pathway in regulating Nrf2-dependent antioxidant functions in the RPE. Invest Ophthalmol Vis Sci 49:1671-8
He, Min; Cai, Jiyang; Go, Young-Mi et al. (2008) Identification of thioredoxin-2 as a regulator of the mitochondrial permeability transition. Toxicol Sci 105:44-50
Chen, Yan; Sternberg, Paul; Cai, Jiyang (2008) Characterization of a Bcl-XL-interacting protein FKBP8 and its splice variant in human RPE cells. Invest Ophthalmol Vis Sci 49:1721-7
Chen, Yan; Cai, Jiyang; Jones, Dean P (2006) Mitochondrial thioredoxin in regulation of oxidant-induced cell death. FEBS Lett 580:6596-602