The major focus of our laboratory is the study of the molecular mechanisms of neuronal dysfunction and 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 ischemic stroke. 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 β-amyloid toxicity, neurotrophin-withdrawal-induced death and in vivo models of ischemia and diabetic macular edema. We have developed specific molecular tools for knocking down individual members of the death pathways in post-mitotic (neuronal) cells and for blocking caspase activity/activation in cultured neurons 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.
Jean YY, Ribe EM, Pero ME, Moskalenko M*, Iqbal Z*, Marks LJ*, Greene LA and Troy CM
. (2013) Caspase-2 is essential for c-Jun transcriptional activation and Bim induction in neuron death. Biochem J.;455(1):15-25
Pozueta J, Lefort R, Ribe EM, Troy CM
, Arancio O, Shelanski M. Caspase-2 is required for dendritic spine and behavioural alterations in J20 APP transgenic mice. Nat Commun. 2013;4:1939. doi: 10.1038/ncomms2927.
Ribe EM, Jean YY, Goldstein, RL*, Manzl, C, Stefanis, L, Villunger, A, and Troy, CM
. (2012) Neuronal caspase-2 activity and function requires RAIDD, but not PIDD. Biochem J. 444, 591-599 (2012)
Tamayev R, Akpan N, Arancio O, Troy CM
, D'Adamio L. (2012) “Caspase-9 mediates synaptic plasticity and memory deficits of Danish dementia knock-in mice: caspase-9 inhibition provides therapeutic protection.” Mol Neurodegener. 10.1186/1750-1326-7-60.
Akpan, N., Serrano-Saiz, E., Zacharia, B.E., Otten, M.L., Ducruet, A.F., Snipas, S.J., Liu, W.,* Velloza, J.*, Cohen, G., Sosunov, S.A., Frey, W.F., Salvesen, G.S., Connolly Jr, E.S., Troy, CM
. (2011) “Intranasal delivery of caspase-9 inhibitor reduces caspase-6-dependent axon/neuron loss and improves neurological function after stroke”. J Neurosci. 31:8894-8904.
Puzzo, D., Privitera, L., Fa’, M., Staniszewski, A., Hashimoto, G., Aziz, F., Sakurai, M., Ribe, E. M., Troy, C.M.
, Mercken, M., Jung, S. S., Palmeri, A. and Arancio, O. (2011) “Endogenous amyloid-β is necessary for hippocampal synaptic plasticity and memory” Ann. Neurol. 69:819-30Troy, C. M.
, Akpan, N. and Jean, Y.Y. (2011) “Regulation of Caspases in the Nervous System: Implications for functions in health and disease” Proteases in Health and Disease, ed. E. Di Cera Prog Mol Biol Transl Sci. 99C:265-305.
Ribe Garrido, E, Heidt, L*, Beaubier, N and Troy C. M.
(2011) “Molecular Mechanisms of Neuronal Death” Advances in Neurobiology, vol 1, Neurochemical Mechanisms of Disease ed. Blass, JP, pages 17-48.
Siddiq A, Aminova LR, Troy CM
, Suh K, Messer Z, Semenza GL, Ratan RR. Selective inhibition of hypoxia-inducible factor (HIF) prolyl-hydroxylase 1 mediates neuroprotection against normoxic oxidative death via HIF- and CREB-independent pathways. J Neurosci. (2009) Jul 8;29(27):8828-38.
Ho CC, Rideout HJ, Ribe E, Troy CM
, Dauer WT. The Parkinson disease protein leucine-rich repeat kinase 2 transduces death signals via Fas-associated protein with death domain and caspase-8 in a cellular model of neurodegeneration. J Neurosci. (2009) Jan 28;29(4):1011-6.Troy CM
, Ribe EM. Caspase-2: vestigial remnant or master regulator? Sci Signal. (2008) Sep 23;1(38):pe42.
Ribe EM, Serrano-Saiz E, Akpan N, Troy CM
. Mechanisms of neuronal death in disease: defining the models and the players. Biochem J. (2008) Oct 15;415(2):165-82. Review.
Biswas SC, Shi Y, Vonsattel JP, Leung CL, Troy CM
, Greene LA. Bim is elevated in Alzheimer's disease neurons and is required for beta-amyloid-induced neuronal apoptosis. J Neurosci. (2007) Jan 24;27(4):893-900.
Greene LA, Liu DX, Troy CM
, Biswas SC. Cell cycle molecules define a pathway required for neuron death in development and disease. Biochim Biophys Acta. (2007) Apr;1772(4):392-401. Epub 2006 Dec 13. Review.
Davidson, T. J., Harel, S., Arboleda, V. A., Shelanski, M. L., Greene, L. A. and Troy CM
. Highly efficient siRNA delivery to primary mammalian neurons induces microRNA-like effects before mRNA degradation. 2004 J. Neurosci 24:10040-10046.