Dysregulation of cellular Zn2+ has been tightly linked to neuronal injury in neurodegenerative conditions present in stroke, trauma and epilepsy. Our group first suggested that Zn2+ released from intracellular binding proteins by oxidative and nitrosative stress represents a critical and ubiquitous component in the activation of neuronal cell death processes in these and other neurological disorders. In work performed during the first funding period of this grant, we characterized cell death signaling cascades accompanied by intracellular Zn2+ liberation, and demonstrated in vivo injurious intraneuronal accumulation of this metal in the absence of synaptic Zn2+ release. The completion and publication of nearly all of the originally proposed experiments has allowed us to continue to expand our work in this novel and exciting area of research. In this competitive renewal application we propose: 1) To establish the mechanism by which intracellular Zn2+ release activates specific MAPK-dependent cell death signaling pathways. With these studies, we aim to eventually characterize the process by which Zn2+ can initiate divergent signaling processes. 2) To investigate the factors that modulate Zn2+-regulated neuronal gene expression in order to resolve conditions affecting Zn2+ buffering systems and, ultimately, Zn2+ cellular homeostasis. These studies aim to elucidate the fundamental properties of Zn2+-mediated gene expression in neurons, a relatively unexplored but critically important area of research. And 3) to determine the molecular cell-death pathway activated by intracellular Zn2+ release in vivo and uncover the endogenous stimulus for the liberation of this metal. Our long-term objectives are to characterize in detail the molecular signaling cascades leading to neuronal cell death following the liberation of intracellular Zn2+. As such, results of these studies will likely generate new avenues for therapeutic intervention in the large number of neurodegenerative disorders associated with oxidative and nitrosative injury.

Public Health Relevance

Results from these studies will provide fundamental information about the cellular mechanisms responsible for a host of neurological disorders, including stroke, trauma and epilepsy. With this information, we hope to uncover novel therapeutic strategies to prevent or halt the progression of these and other neurodegenerative conditions.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Neural Oxidative Metabolism and Death Study Section (NOMD)
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Jacobs, Tom P
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University of Pittsburgh
Schools of Medicine
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Justice, Jason A; Manjooran, Daniel T; Yeh, Chung-Yang et al. (2018) Molecular Neuroprotection Induced by Zinc-Dependent Expression of Hepatitis C-Derived Protein NS5A Targeting Kv2.1 Potassium Channels. J Pharmacol Exp Ther 367:348-355
Justice, Jason A; Schulien, Anthony J; He, Kai et al. (2017) Disruption of KV2.1 somato-dendritic clusters prevents the apoptogenic increase of potassium currents. Neuroscience 354:158-167
Yeh, Chung-Yang; Bulas, Ashlyn M; Moutal, Aubin et al. (2017) Targeting a Potassium Channel/Syntaxin Interaction Ameliorates Cell Death in Ischemic Stroke. J Neurosci 37:5648-5658
Schulien, Anthony J; Justice, Jason A; Di Maio, Roberto et al. (2016) Zn(2+) -induced Ca(2+) release via ryanodine receptors triggers calcineurin-dependent redistribution of cortical neuronal Kv2.1 K(+) channels. J Physiol 594:2647-59
Li, Dong; Yuan, Hongjie; Ortiz-Gonzalez, Xilma R et al. (2016) GRIN2D Recurrent De Novo Dominant Mutation Causes a Severe Epileptic Encephalopathy Treatable with NMDA Receptor Channel Blockers. Am J Hum Genet 99:802-816
Clemens, Katerina; Yeh, Chung-Yang; Aizenman, Elias (2015) Critical role of Casein kinase 2 in hepatitis C NS5A-mediated inhibition of Kv2.1 K(+) channel function. Neurosci Lett 609:48-52
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He, Kai; McCord, Meghan C; Hartnett, Karen A et al. (2015) Regulation of Pro-Apoptotic Phosphorylation of Kv2.1 K+ Channels. PLoS One 10:e0129498
Hershfinkel, Michal; Ford, Dianne; Kelleher, Shannon et al. (2015) Seashells by the zinc shore: a meeting report of the International Society for Zinc Biology, Asilomar, CA 2014. Metallomics 7:1299-304
Gilad, David; Shorer, Sharon; Ketzef, Maya et al. (2015) Homeostatic regulation of KCC2 activity by the zinc receptor mZnR/GPR39 during seizures. Neurobiol Dis 81:4-13

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