This study will focus on the fundamental question of whether reactive metabolites of dopamine, may be contributing to the pathogenesis of neurodegenerative disorders such as Parkinson's disease. Dopamine has been shown to be toxic to cells both in vitro and in vivo. However, the exact mechanism associated with the toxicity is not known. Because mitochondria play a critical role in mechanisms of cell death, the proposed studies are designed to increase our understanding of the interplay between reactive metabolites of dopamine and mitochondrial function, and their ability to enhance the vulnerability of dopaminergic neurons to injury.
In Aim 1, we will characterize the temporal relationship between loss of mitochondrial function and cell death following exposure to dopamine.
In Aim 2, using striatonigral organotypic cultures, we will examine whether dopaminergic neurons exhibit an increased vulnerability to mitochondrial inhibition and whether dopamine contributes to this effect. Finally, in Aim 3, we will determine the identity of critical proteins modified and inactivated by dopamine quinones using mass spectrometry, with a focus on mitochondrial proteins. The outcome of these studies has potential for identifying new therapeutic targets for stopping and preventing the neurodegenerative process in Parkinson's disease.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-MDCN-2 (01))
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Sheehy, Paul A
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University of Pittsburgh
Schools of Medicine
United States
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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
Hastings, Teresa G (2009) The role of dopamine oxidation in mitochondrial dysfunction: implications for Parkinson's disease. J Bioenerg Biomembr 41:469-72
Van Laar, Victor S; Mishizen, Amanda J; Cascio, Michael et al. (2009) Proteomic identification of dopamine-conjugated proteins from isolated rat brain mitochondria and SH-SY5Y cells. Neurobiol Dis 34:487-500
Dukes, April A; Van Laar, Victor S; Cascio, Michael et al. (2008) Changes in endoplasmic reticulum stress proteins and aldolase A in cells exposed to dopamine. J Neurochem 106:333-46
Van Laar, Victor S; Dukes, April A; Cascio, Michael et al. (2008) Proteomic analysis of rat brain mitochondria following exposure to dopamine quinone: implications for Parkinson disease. Neurobiol Dis 29:477-89
Chen, Linan; Ding, Yunmin; Cagniard, Barbara et al. (2008) Unregulated cytosolic dopamine causes neurodegeneration associated with oxidative stress in mice. J Neurosci 28:425-33
Signore, Armando P; Weng, Zhongfang; Hastings, Teresa et al. (2006) Erythropoietin protects against 6-hydroxydopamine-induced dopaminergic cell death. J Neurochem 96:428-43
Dukes, April A; Korwek, Kimberly M; Hastings, Teresa G (2005) The effect of endogenous dopamine in rotenone-induced toxicity in PC12 cells. Antioxid Redox Signal 7:630-8
Perez, Ruth G; Hastings, Teresa G (2004) Could a loss of alpha-synuclein function put dopaminergic neurons at risk? J Neurochem 89:1318-24