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

Research Summary
The major focus of our laboratory is the study of the molecular mechanisms of neuronal death with an emphasis on the regulation of caspase activity.

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 multi-membered family of death proteases that are central to the execution of death. Current death paradigms under study include b-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 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-1b 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 interaction that can occur between the cytokine signaling pathway and the death pathway to determine the appropriate intervention that will result in increased neuronal survival.

1. 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.

2. Troy, C.M., Stefanis, L., Prochiantz, A., Greene, L.A. and Shelanski, M.L. (1996). The contrasting roles of ICE-family proteases and interleukin-1b in apoptosis induced by trophic factor withdrawal and by SOD1 downregulation. Proc. Natl. Acad. Sci. U.S.A. 93:

3. 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 b-Amyloid” J. Neurosci. 20:1386-1392.

4. 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 -9 pathways in neuronal death induced by NGF-deprivation" J. Neurosci. 21:5007-5016.

5. Troy, C. M., Friedman, J. E. and Friedman, W. J. (2002) “Mechanisms of p75-Mediated Death of Hippocampal Neurons: Role of Caspases. J. Biol. Chem. 277: 34295-34302

6. Troy, C. M. and Shelanski, M.L. (2003) “Caspase-2 Redux” Cell Death and Differentiation 10: 101-7

1. Downstream Regulators of b-amyloid Induced Neuronal Death
The major goals of this project are to determine the molecular mechanisms of b-amyloid-induced neuronal death. The specific aims are: 1. To determine which caspases are activated and which execute Ab and TFD mediated death. 2. To determine whether there is differential expression and regulation of MIAP3 or Diablo after Ab or TFD. 3. To determine whether activation of the JNK cascade leads to caspase-2 activation.
National Institute of Neurological Disorders and Stroke
7/2001 - 6/2005

2. Mechanisms of neuronal hypoglycemic injury
Role: co-PI (PI: Salton)
The major goals of this project are to better define how neurons are damaged by hypoglycemia in the nervous system, whether synaptic connectivity and neuronal development are affected, and whether hypoglycemia triggers expression of particular genes within the developing brain, providing insight into the type of damage that is sustained.
National Institute of Neurological Disorders and Stroke/National Institute of Diabetes and Digestive and Kidney Diseases
9/2002 - 9/2006

1. Neuronal Degeneration: Mechanisms and Prevention
This major goals of this project are to 1. To determine how NO mediates free radical induced neuronal cell death. 2. To determine how IL-1b mediates cell death induced by the down-regulation of SOD1 while it has no deleterious effects in the trophic factor deprivation paradigm.
Agency: NIH/NINDS
Period: 6/10/97-4/30/02

Committee/Council Memberships
Member NIH- MDCN2 Study Section
Member Editorial Advisory Board Biochemical Journal
American Association for the Advancement of Science
The Society for Neuroscience
The International Cell Death Society
The International Society for Developmental Neuroscience

Keywords: Alzheimer's disease, amyloid protein, apoptosis, cell death, cell growth regulation, cysteine endopeptidase, cytotoxicity, growth factor, neuron, JUN kinase, brain, enzyme activity, gene expression, transport protein, PC12 cell, clinical research, human tissue, immunocytochemistry, in situ hybridization, laboratory mouse, tissue /cell culture, transgenic animal, western blotting, cell death, apoptosis, neuronal death, caspases, caspase regulation, IAPs, cytokine-mediated neuronal death