[Pathology Graduate Program] Carol M. Troy, M.D., Ph.D.

Department of Pathology

Carol M. Troy, M.D., Ph.D.

THE MOLECULAR MECHANISMS OF NEURONAL DEATH

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.

We have developed specific molecular tools for knocking down individual members of the death pathways in post-mitotic (neuronal) cells. 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 relativeccconcentrations 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-ί 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.

Selected Publications:

Proc. Natl. Acad. Sci. USA

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. J. Neurosci. 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-1ί in apoptosis induced by trophic factor withdrawal and by SOD1 downregulation. Proc. Natl. Acad. Sci. U.S.A. 93: 5635-5640.

Troy, C.M. Stefanis, L., Greene, L. A., and Shelanski, M. L. (1997) Nedd2 is required for apoptosis following trophic factor withdrawal but not SOD1 down-regulation in sympathetic neurons and PC12 cells. J. Neurosci117:1911-1918.

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" J. Neurosci. 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" J. Neurosci.21:5007-5016

Troy, C. M. "Caspase Specificity in Neuronal Death" (2002) in Neuroprotection Marwarh, J. and Lo, E. eds. Prominent Press. p. 281-298.

[Go to start of Document ]

May 2002