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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Program Projects (P01)
Project #
Application #
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pittsburgh
United States
Zip Code
Di Maio, Roberto; Barrett, Paul J; Hoffman, Eric K et al. (2016) α-Synuclein binds to TOM20 and inhibits mitochondrial protein import in Parkinson's disease. Sci Transl Med 8:342ra78
Hu, Xiaoming; Leak, Rehana K; Shi, Yejie et al. (2015) Microglial and macrophage polarization—new prospects for brain repair. Nat Rev Neurol 11:56-64
Zharikov, Alevtina D; Cannon, Jason R; Tapias, Victor et al. (2015) shRNA targeting α-synuclein prevents neurodegeneration in a Parkinson's disease model. J Clin Invest 125:2721-35
Lee, Jang-Won; Tapias, Victor; Di Maio, Roberto et al. (2015) Behavioral, neurochemical, and pathologic alterations in bacterial artificial chromosome transgenic G2019S leucine-rich repeated kinase 2 rats. Neurobiol Aging 36:505-18
An, Chengrui; Shi, Yejie; Li, Peiying et al. (2014) Molecular dialogs between the ischemic brain and the peripheral immune system: dualistic roles in injury and repair. Prog Neurobiol 115:6-24
Hu, Xiaoming; Liou, Anthony K F; Leak, Rehana K et al. (2014) Neurobiology of microglial action in CNS injuries: receptor-mediated signaling mechanisms and functional roles. Prog Neurobiol 119-120:60-84
Tapias, Victor; Greenamyre, J Timothy (2014) A rapid and sensitive automated image-based approach for in vitro and in vivo characterization of cell morphology and quantification of cell number and neurite architecture. Curr Protoc Cytom 68:12.33.1-22
Zhao, Shangfeng; Li, Fengwu; Leak, Rehana K et al. (2014) Regulation of Neuroinflammation through Programed Death-1/Programed Death Ligand Signaling in Neurological Disorders. Front Cell Neurosci 8:271
Wang, Jiayin; Shi, Yejie; Zhang, Lili et al. (2014) Omega-3 polyunsaturated fatty acids enhance cerebral angiogenesis and provide long-term protection after stroke. Neurobiol Dis 68:91-103
Mohammadyani, Dariush; Tyurin, Vladimir A; O'Brien, Matthew et al. (2014) Molecular speciation and dynamics of oxidized triacylglycerols in lipid droplets: Mass spectrometry and coarse-grained simulations. Free Radic Biol Med 76:53-60

Showing the most recent 10 out of 38 publications