TY - JOUR T1 - Molecular neuroprotection induced by zinc-dependent expression of hepatitis C-derived protein NS5A targeting Kv2.1 potassium channels JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.118.252338 SP - jpet.118.252338 AU - Jason A Justice AU - Daniel T Manjooran AU - Chung-Yang Yeh AU - Karen A Hartnett-Scott AU - Anthony J Schulien AU - Gabrielle J Kosobucki AU - Shalom Mammen AU - Michael J Palladino AU - Elias Aizenman Y1 - 2018/01/01 UR - http://jpet.aspetjournals.org/content/early/2018/09/06/jpet.118.252338.abstract N2 - We present the design of an innovative molecular neuroprotective strategy, and provide proof-of-concept for its implementation, relying on the injury-mediated activation of an ectopic gene construct. As oxidative injury leads to the intracellular liberation of zinc, we hypothesize that tapping onto the zinc-activated metal regulatory element (MRE) transcription factor 1 (MTF-1) system to drive expression of the Kv2.1-targeted hepatitis C protein NS5A, will provide neuroprotection by preventing cell death-enabling cellular potassium loss in rat cortical neurons in vitro. Indeed, using biochemical and morphological assays, we demonstrate rapid expression of MRE-driven products in neurons. Further, we report that MRE-driven NS5A expression, induced by a slowly evolving excitotoxic stimulus, functionally blocks injurious, enhanced Kv2.1 potassium whole-cell currents and improves neuronal viability. We suggest this form of "on-demand" neuroprotection could provide the basis for a tenable therapeutic strategy to prevent neuronal cell death in neurodegeneration. ER -