Neuronal Injury Research
Stroke is the third leading cause of death in the US and is a leading cause of morbidity. Ischemic stroke results from a thromboembolic event causing decreased cerebral perfusion. While advances have been made regarding the cellular and molecular basis of ischemic injury, it has proven difficult to translate this knowledge into treatments that improve recovery. Thrombolytic therapies, such as the administration of tPA are currently the only effective treatment available. Although these treatments reduce stroke damage and improve outcomes, patients are often left disabled. Furthermore, the majority of patients are not candidates for mechanical or pharmacologic thrombolysis. Thus it is critical to identify the biochemical mechanisms underlying stroke-related damage so that treatments may be developed to help improve recovery.
Ischemia triggers a series of pathological events in the brain leading to subsequent neuronal loss by apoptosis and other mechanisms of cellular injury. Severe ischemia causes neurons to undergo irreversible membrane depolarization and immediate cell swelling, while mild ischemia induces slow excitotoxicity and neurodegeneration. These two processes account for both the early neuronal loss observed in the ischemic core and the delayed damage in the surrounding penumbra. At the cellular level, the ion exchange balance across the cell membrane is damaged, disrupting normal cellular processes like oxidative phosphorylation required for respiration, resulting in depolarization of the cell membrane. Excitotoxic glutamatergic neurotransmission ensues, triggering the activation of proteases, phosphatases, phospholipases, and free radical actions.
Excitotoxic glutamate released during ischemia may activate NMDA receptors resulting in Ca2+ overload. Consequently, Ca2+-activation of the cysteine protease, calpain, contributes to ischemic damage. A key substrate of calpain is p35, the activating cofactor of neuronal protein kinase Cdk5. Under physiological conditions, Cdk5/p35 is involved in an array of neuronal processes including the regulation of dopaminergic neurotransmission. However, calpain-dependent conversion of Cdk5/p35 to Cdk5/p25 has neurotoxic effects and has been implicated in various neurodegenerative diseases.
We have been studying the role of Cdk5 in mediating neuronal injury induced by neurotoxicity, ischemia, and tramatic brain injury. Our goal is to understand how aberrant Cdk5 contributes across the spectrum to neuronal insult and determine the key pathways by which Cdk5 contributes to neuronal cell loss of function and death. The models we are studying include middle cerebral artery occlusion, traumatic brain injury, and neurotoxicant exposure.
See the following publication to learn more about our mood disorder research:
Torres-Altoro, M.I., Mathur, B.N., Drerup, J.M., Thomas, R., Lovinger, D., O’Callaghan, J.P., Bibb, J.A. (2011) Orthophosphates dysregulated dopamine signaling, glutamaterigic neurotransmission, and induce neuronal injury markers in striatum, Journal of Neurochemistry. 119:303-13
Xu, J., Kurup, P., Zhang, Y., Hawasli, A.H., Bibb, J.A., and Lombroso, P.J. (2009) Striatal-enriched protein tyrosine phosphatase (STEP) is neuroprotective against excitotoxicity, J. Neurosci 29: 9330-43.
Lagace, D.C., Benavides, D.R., Kansy, J.W. Mapelli, M., Greengard,P., Bibb, J.A. Eisch, A.J. (2008) Cdk5 is essential for adult hippocampal neurogenesis, PNAS 105:18567–18571.
Hayashi, K., Pan, Y. Shu, H., Kansy, J.W., White, C.L., Tamminga, C.A., Sobel, A., Curmi, P.A., Mikoshiba, K. and Bibb, J.A. (2006) Phosphorylation of the tubulin binding protein stathmin by Cdk5 and MAP kinases in the brain. J. Neurochem. 99: 237-250.
LeClerc, S, Garnier, M., Hoessel, R., Marko, D., Bibb, J.A., Mandelkow, E.-M., Eisenbrand, G., and Meijer, L. (2000) Indirubins inhibit glycogen synthase kinase-3b and cdk5/p35, two protein kinases involved in abnormal tau phosphorylation in Alzheimer’s disease – A property common to most cdk inhibitors? J. Biol. Chem. 276: 251-260.
Barnett, D.G.S. and Bibb, J.A. (2010) The role of Cdk5 signaling in cognition and neuropsychiatric and neurological pathology, Brain Research Bullitin, 85:9-13.