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)
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National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
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University of Pittsburgh
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Verma, Manish; Callio, Jason; Otero, P Anthony et al. (2017) Mitochondrial Calcium Dysregulation Contributes to Dendrite Degeneration Mediated by PD/LBD-Associated LRRK2 Mutants. J Neurosci 37:11151-11165
Tapias, Victor; Hu, Xiaoping; Luk, Kelvin C et al. (2017) Synthetic alpha-synuclein fibrils cause mitochondrial impairment and selective dopamine neurodegeneration in part via iNOS-mediated nitric oxide production. Cell Mol Life Sci 74:2851-2874
Di Maio, Roberto; Barrett, Paul J; Hoffman, Eric K et al. (2016) ?-Synuclein binds to TOM20 and inhibits mitochondrial protein import in Parkinson's disease. Sci Transl Med 8:342ra78
Van Laar, Victor S; Berman, Sarah B; Hastings, Teresa G (2016) Mic60/mitofilin overexpression alters mitochondrial dynamics and attenuates vulnerability of dopaminergic cells to dopamine and rotenone. Neurobiol Dis 91:247-61
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
Greenamyre, J Timothy; Sanders, Laurie H; Gasser, Thomas (2015) Fruit flies, bile acids, and Parkinson disease: a mitochondrial connection? Neurology 85:838-9
Zharikov, Alevtina D; Cannon, Jason R; Tapias, Victor et al. (2015) shRNA targeting ?-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
Tapias, Victor; Cannon, Jason R; Greenamyre, J Timothy (2014) Pomegranate juice exacerbates oxidative stress and nigrostriatal degeneration in Parkinson's disease. Neurobiol Aging 35:1162-76
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

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