MicroRNA-223 protects neurons from degeneration in experimental autoimmune encephalomyelitis.

TitleMicroRNA-223 protects neurons from degeneration in experimental autoimmune encephalomyelitis.
Publication TypeJournal Article
Year of Publication2019
AuteursMorquette, B, Juźwik, CA, Drake, SS, Charabati, M, Zhang, Y, Lécuyer, M-A, Galloway, DA, Dumas, A, Junior, Ode Faria, Paradis-Isler, N, Bueno, M, Rambaldi, I, Zandee, S, Moore, C, Bar-Or, A, Vallières, L, Prat, A, Fournier, AE
JournalBrain
Volume142
Issue10
Pagination2979-2995
Date Published2019 10 01
ISSN1460-2156
KeywordsAnimals, Axons, Disease Models, Animal, Encephalomyelitis, Autoimmune, Experimental, Glutamic Acid, Humans, Leukocytes, Mononuclear, Mice, MicroRNAs, Multiple Sclerosis, Nerve Degeneration, Neurodegenerative Diseases, Neurons, Rats, Rats, Sprague-Dawley, RNA, Messenger, Signal Transduction, Spinal Cord
Abstract

Multiple sclerosis is a chronic inflammatory, demyelinating, and neurodegenerative disease affecting the brain, spinal cord and optic nerves. Neuronal damage is triggered by various harmful factors that engage diverse signalling cascades in neurons; thus, therapeutic approaches to protect neurons will need to focus on agents that can target multiple biological processes. We have therefore focused our attention on microRNAs: small non-coding RNAs that primarily function as post-transcriptional regulators that target messenger RNAs and repress their translation into proteins. A single microRNA can target many functionally related messenger RNAs making microRNAs powerful epigenetic regulators. Dysregulation of microRNAs has been described in many neurodegenerative diseases including multiple sclerosis. Here, we report that two microRNAs, miR-223-3p and miR-27a-3p, are upregulated in neurons in the experimental autoimmune encephalomyelitis mouse model of CNS inflammation and in grey matter-containing multiple sclerosis lesions. Prior work has shown peripheral blood mononuclear cell conditioned media causes sublethal degeneration of neurons in culture. We find overexpression of miR-27a-3p or miR-223-3p protects dissociated cortical neurons from condition media mediated degeneration. Introduction of miR-223-3p in vivo in mouse retinal ganglion cells protects their axons from degeneration in experimental autoimmune encephalomyelitis. In silico analysis revealed that messenger RNAs involved in glutamate receptor signalling are enriched as miR-27a-3p and miR-223-3p targets. We observe that antagonism of NMDA and AMPA type glutamate receptors protects neurons from condition media dependent degeneration. Our results suggest that miR-223-3p and miR-27a-3p are upregulated in response to inflammation to mediate a compensatory neuroprotective gene expression program that desensitizes neurons to glutamate by targeting messenger RNAs involved in glutamate receptor signalling.

DOI10.1093/brain/awz245
Alternate JournalBrain
PubMed ID31412103
Grant List / / Canadian Institutes for Health Research / International