MicroRNA-9 Targets the Neuroprotective Enzyme Glutamate Oxaloacetate Transaminase
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Date
2016-05
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The Ohio State University
Abstract
Glutamate serves multifaceted physiological functions in the CNS as the most abundant excitatory neurotransmitter and under pathological conditions as a potent neurotoxin. Elevated extracellular glutamate is known to play a central role in ischemic brain injury. The current study stems from our key observation demonstrating that induction of glutamate oxaloacetate transaminase (GOT), a glutamate-metabolizing enzyme in the brain, can attenuate stroke-induced injury. From the historical work of Hans Krebs, we know that GOT metabolism of glutamate generates TCA cycle intermediates in brain tissue. GOT catalyzes the transfer of the amino group from glutamate to the 4-carbon TCA cycle intermediate oxaloacetate to generate aspartate and the 5-carbon TCA cycle intermediate α-ketoglutarate. We thus proposed in a previous study that induction of GOT can utilize otherwise neurotoxic glutamate to support survival of ischemic glucose-starved neural cells. The aim of the current work is to identify the mechanisms of GOT induction. Emergent literature supports microRNAs (miRNAs) as key mediators of post-transcriptional gene silencing. MicroRNAs comprise a novel class of small, noncoding endogenous RNAs that regulate gene expression by targeting mRNAs for degradation or translational repression. MicroRNA-9 (miR-9) is abundantly expressed in the brain, where it is predicted to target genes involved in glutamate metabolism. In the current work, we hypothesize that miR-9 targets GOT, resulting in post-transcriptional gene silencing. Furthermore, we hypothesize that inhibition of miR-9 upregulates GOT expression and enhances its neuroprotective properties. We recognize a therapeutic opportunity in which inhibition of miR-9 could potentially lead to improved outcome for ischemic stroke patients.
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Keywords
MicroRNA-9, MicroRNA, Ischemic Stroke, GOT, Glutamate Oxaloacetate Transaminase, miR-9