Selenoproteins play a critical role in the antioxidant defense of the brain. However, the selenocysteine residue at the catalytic active site of selenoproteins will be highly susceptible to oxidation and covalent modification by dopamine quinone, resulting inactivation of the protein function. Loss of key mitochondrial selenoprotein functions will increase the vulnerability of dopaminergic neurons to degeneration through the accumulation of oxidative damage in neurons. This proposal is designed to examine changes in the expression and activity of mitochondrial GPX4 (glutathione peroxidase 4 or phosphohpid hydroperoxide glutathione peroxidase) and TrxR2 (mitochondrial thioredoxin reductase 2) following toxin exposure, and whether alterations in the levels of these proteins affect neuronal vulnerability to toxins. We hypothesize that decreased selenoprotein function (GPX4, TrxR2), which may occur selectively in dopamine (DA) neurons, will increase oxidative stress and mitochondrial dysfunction, resulting cell death in Parkinson's disease (PD) toxin models such as rotenone, 6- OHDA, and DA-induced toxicity. This project has the following Aims: 1. To examine whether DA oxidation and DA quinone formation targets selenocysteine residues resulting in covalent modification and inactivation of selenoproteins. 2. (a.) To examine whether exposure to PD toxins (rotenone, DA, 6-OHDA) in vitro and in vivo alters mitochondrial selenoprotein (GPX4, TrxR2) levels. (b.) To examine whether selenoprotein expression and localization are altered in human PD substantia nigra (SN) as compared to age-matched controls. 3. To examine whether changes in selenoprotein expression affect the vulnerability of dopaminergic neurons to toxic insults. 4. To examine whether the loss of selenoprotein P (SelP) in brain results in dysfunction and/or degeneration of nigrostriatal dopaminergic neurons. Through the use of the Molecular and Neuropathology Cores - and with extensive interactions vrith other projects in this Program - this project will elucidate the roles of mitochondrial selenoproteins in the pathogenesis of PD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
5P01NS059806-05
Application #
8505553
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2013
Total Cost
$245,156
Indirect Cost
$83,336
Name
University of Pittsburgh
Department
Type
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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