One research goal is to understand the effects of long-term ethanol exposure on signal transduction in neuronal systems. Long-term ethanol down regulates phospholipase D activity but does not appear to affect the phospholipase C specific for inositol-containing phospholipids. The differential effects of ethanol are due to the uniqueness of each signal transduction pathway. For example, the activation of phospholipase D is mediated by tyrosine kinases, whereas the activation of phospholipase C is mediated by G-proteins. Current research is focused on the role of phosphorylation in mediating the inhibitory effects of ethanol.
Another research goal is to understand the role of free radicals in the etiology of Parkinson’s disease and other neurodegenerative diseases. We are particularly interested in peroxynitrite-mediated toxicity to catecholamine containing cells. Peroxynitrite is an oxygen reactive molecule that is formed by the near diffusion-limited reaction of superoxide with nitric oxide. These metabolites are found at high concentrations in the substantia nigra, the area that degenerates in Parkinson’s. Initial studies suggest that peroxynitrite inhibits tyrosine hydroxylase by nitration of a single tyrosine residue near the active site of the enzyme. We have also shown that tyrosine hydroxylase is nitrated in an animal model for Parkinson’s. The inactivation of tyrosine hydroxylase represents the initial insult in the progression of this neurodegenerative disease.
"Differential effects of long-term ethanol on signal transduction in PC12 cells"
Levine, G., Magliano, J., and Horwitz, J.
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"Nitration of a single tyrosine residue accelerates proteolytic degradation of proteins"
Souza, J.M. Choi, I., Chen, Q., Daikhin, E., Yudkoff, M., Obin, M., Ara, J., Horwitz, J., and Ischiropoulos, H.
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"Phospholipase D hydrolyzes short-chain analogs of phosphatidylcholine in the absence of detergent"
Horwitz, J., Magliano, J., and Davis, L.L.
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"Increased levels of methylated intermediates of phosphatidylcholine lead to enhanced phospholipase D activity"
Jacobs, T.Q., Passarello, B., and Horwitz, J.
Neurochem Res. 23 1101-1107 (1998).
"Nitration and inactivation of tyrosine hydroxylase at early stages of 1-methyl-4-pheny-1,2,3,6-tetrahydropyridine neurotoxicity: A novel biochemical mechanism for Parkinson’s disease"
Ara, J., Horwitz, J., Jackson-Lewis, V., Naini, A.B., Przedborski, S., Gole, M., Malcolm, S., Faust, R., Gow, A., Ischiropoulos, H.
Proc. Natl. Acad. Sci. USA 95 7659-7663 (1998).
"Peroxynitrite-mediated inhibition of DOPA synthesis in PC12 cells"
Ischiropoulos, H., Duran, D., and Horwitz, J.
J. Neurochem. 65 2366-2372 (1995).