The major focus of our laboratory is the study of the molecular mechanisms of neuronal death. Neuronal loss is an outstanding feature of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. We employ model systems of neuronal death to define the death pathways. We are particularly interested in the regulation of the caspases, the family of proteases that are central to the execution of death. Current death paradigms under study include beta-amyloid toxicity, peroxynitrite-mediated death and neurotrophin-withdrawal-induced death and a mouse model of ischemia.

We have developed specific molecular tools for knocking down individual members of the death pathways in post-mitotic (neuronal) cells in vitro and in vivo. We have shown that the specificity of the death pathway is determined by the stimulus inducing death but also that there is flexibility in the pathways chosen for executing death. The dominant pathway depends on the relative concentrations of anti- and pro-apoptotic proteins. This illustrates that the maintenance of life and execution of death of a neuron is a delicate balance of the pro- and anti-apoptotic molecules in the cell, a balance that can be altered in disease.

Our studies of oxidative stress-mediated death show that cytokines can induce an autocrine mediated death. Down-regulation of superoxide dismutase 1 leads to activation of caspase-1 which releases the cytokine interleukin-1-beta and the cells undergo a peroxynitrite-dependent death. Thus, although caspase-1 has been defined as a non-apoptotic caspase with a role in inflammation, in response to specific death stimuli caspase-1 can activate a death pathway. It is important to understand the interactions that can occur between the cytokine signaling pathway and the death pathway to determine the appropriate intervention that will result in increased neuronal survival.  These studies are now being extended to a mouse model of ischemia.

Selected Recent Publications:

• Troy, C.M., Derossi, S., Prochiantz, A., Greene, L.A. and Shelanski, M.L. (1996). Down-regulation of SOD1 leads to cell death by the NO-peroxynitrite pathway. Journal of Neuroscience. 16: 253-261.
• Troy, C.M., Stefanis, L., Prochiantz, A., Greene, L.A. and Shelanski, M.L. (1996). The contrasting roles of ICE-family proteases and interleukin-1beta in apoptosis induced by trophic factor withdrawal and by SOD1 downregulation. Proc. Natl. Acad. Sci. U.S.A. 93: 5635-5640.
• Troy, C. M., Rabacchi, S. A., Friedman, W. J., Frappier, T. F., Brown, K. and Shelanski, M. L. (2000). "Caspase-2 Mediates Neuronal Cell Death Induced by Beta-Amyloid" Journal of Neuroscience. 20 :1386-1392.
• Troy, C. M., Rabacchi, S. A., Xu, Z. Maroney, A. C., Connors, T. J., Shelanski, M. L. and Greene, L. A. (2001) "Beta-amyloid-induced neuronal apoptosis requires JNK activation" J. Neurochem. 77 :157-64
• Troy, C. M., Rabacchi, S. A., Hohl, J. B., Angelastro, J. M., Greene, L. A. and Shelanski, M. L. (2001) "Death in the balance: Alternative participation of the caspase-2 and caspase-9 pathways in neuronal death induced by NGF-deprivation" Journal of Neuroscience..21:5007-5016.  Troy, C. M., Friedman, J. E. and Friedman, W. J. Mechanisms of p75-Mediated Death of Hippocampal Neurons: Role of Caspases.  J. Biol. Chem. 2002, 277:  34295-34302.
• Rabacchi SA, Friedman WJ, Shelanski ML, Troy CM.  Divergence of the apoptotic pathways induced by 4-hydroxynonenal and amyloid beta-protein. Neurobiol Aging 2004, 25(8):1057-1066.
• Davidson, T. J., Harel, S., Arboleda, V. A., Shelanski, M. L., Greene, L. A. and Troy, C. M.  Highly efficient siRNA delivery to primary mammalian neurons induces microRNA-like effects before mRNA degradation J. Neurosci 2004, 24:10040-10046.
• Wang, Q., Maniati, M., Jabado, O., Pavlaki, M., Troy , C. M., Greene L. A., Stefanis, L. RAIDD is required for apoptosis of PC12 cells and sympathetic neurons induced by trophic factor withdrawal. Cell Death and Differentiation 2006, 13(1):75-83.