Oxidative mechanisms associated with neurodegeneration.
Dr. Hastings’ research focuses on the pathogenesis and treatment of neurodegenerative diseases. Specifically, her work examines the role of oxidative stress in the selective vulnerability of dopaminergic neurons in Parkinson’s disease. Under oxidative conditions, the catechol ring of dopamine will oxidize spontaneously or via enzymatic mechanisms to form reactive oxygen species and dopamine quinones. These metabolites of dopamine will covalently modify cellular proteins and thus have the potential to induce cytotoxicity. Dr. Hastings’ laboratory has shown that injections of dopamine into the striatum of rats leads to the formation of protein cysteinyl-catechols, a product of dopamine oxidation, and results in selective toxicity to dopamine terminals.
Questions currently being examined in her laboratory include what mechanisms are involved in dopamine-induced selective toxicity, the effects of dopamine on mitochondrial dysfunction and using proteomic techniques, what are the proteins modified by dopamine quinones to induce dopaminergic cell death. Other research interests of Dr. Hastings include the role of dopamine, oxidative stress, and mitochondrial dysfunction in the mechanism of methamphetamine-induced toxicity to dopamine terminals. A variety of molecular and immunohistochemical approaches in both in vitro and in vivo models are used in this work.
Van Laar, V.S., Mishizen, J.A., Cascio, M. and Hastings, T.G. Proteomic identification of dopamine-conjugated proteins from isolated rat brain mitochondria and SH-SY5Y cells. Neurobiology of Disease, 2009 (In Press), doi:10.1016/j.nbd.2009.03.004.
Van Laar, V.S., Dukes, A.A., Cascio, M. and Hastings, T.G. Proteomic analysis of rat brain mitochondria following exposure to dopamine quinone: Implications for Parkinson disease. Neurobiol. Dis. 29: 477-489, 2008.
Dukes, A.A., Van Laar, V.S., Cascio, M. and Hastings, T.G. Changes in endoplasmic reticulum stress proteins and aldolase A in cells exposed to dopamine. J. Neurochem. 106: 333-346, 2008. doi:10.1111/j.1471-4159.2008.05392.x
Dukes, A.A., Korwek, K.M., and Hastings, T.G. The effect of endogenous dopamine in rotenone-induced toxicity in PC12 cells. Antioxidants Redox Signal. 7, 630-638, 2005.
Greenamyre, J.T. and Hastings, T.G. Parkinson’s disease: Divergent causes, convergent mechanisms. Science, 304: 1120-1122, 2004
LaVoie, M.J., Card, J.P. and Hastings, T.G. Microglial activation precedes dopamine terminal pathology in methamphetamine-induced neurotoxicity. Exp. Neurol. 187: 47-57, 2004.