AMPK-regulated miRNA-210-3p is activated during ischaemic neuronal injury and modulates PI3K-p70S6K signalling
| Autor: | Anna Tomašcová, Elisabeth Jirström, Bryan T. Hennessy, Alexa Resler, Petronela Weisová, Jochen H. M. Prehn, Mattia Cremona, Heiko Düssmann, Nikolaus Plesnila, Beatrice D'Orsi, Shona Pfeiffer, Niamh M. C. Connolly, Uta Mamrak, Stefan J. Haunsberger, Gang Chen |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Male Primary Cell Culture AMP-Activated Protein Kinases Biochemistry Polymerase Chain Reaction 03 medical and health sciences Cellular and Molecular Neuroscience Phosphatidylinositol 3-Kinases 0302 clinical medicine Tensin PTEN Animals Protein kinase A PI3K/AKT/mTOR pathway Ischemic Stroke Cerebral Cortex Neurons Ribosomal Protein S6 biology Chemistry Kinase Glutamate receptor PTEN Phosphohydrolase AMPK Computational Biology Pyruvate Dehydrogenase Acetyl-Transferring Kinase Ribosomal Protein S6 Kinases 70-kDa Cell biology Enzyme Activation Mice Inbred C57BL MicroRNAs 030104 developmental biology Ribosomal protein s6 biology.protein Female 030217 neurology & neurosurgery Signal Transduction |
| Zdroj: | Journal of neurochemistryReferences. 159(4) |
| ISSN: | 1471-4159 |
| Popis: | Progressive neuronal injury following ischaemic stroke is associated with glutamate-induced depolarization, energetic stress and activation of AMP-activated protein kinase (AMPK). We here identify a molecular signature associated with neuronal AMPK activation, as a critical regulator of cellular response to energetic stress following ischaemia. We report a robust induction of microRNA miR-210-3p both in vitro in primary cortical neurons in response to acute AMPK activation and following ischaemic stroke in vivo. Bioinformatics and reverse phase protein array analysis of neuronal protein expression changes in vivo following administration of a miR-210-3p mimic revealed altered expression of phosphatase and tensin homolog (PTEN), 3-phosphoinositide-dependent protein kinase 1 (PDK1), ribosomal protein S6 kinase (p70S6K) and ribosomal protein S6 (RPS6) signalling in response to increasing miR-210-3p. In vivo, we observed a corresponding reduction in p70S6K activity following ischaemic stroke. Utilizing models of glutamate receptor over-activation in primary neurons, we demonstrated that induction of miR-210-3p was accompanied by sustained suppression of p70S6K activity and that this effect was reversed by miR-210-3p inhibition. Collectively, these results provide new molecular insight into the regulation of cell signalling during ischaemic injury, and suggest a novel mechanism whereby AMPK regulates miR-210-3p to control p70S6K activity in ischaemic stroke and excitotoxic injury. |
| Databáze: | OpenAIRE |
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