Étude des mécanismes sous-jacents la neurodégénérescence et la neuroprotection axonale dans un modèle de sclérose en plaque via la modulation de microARN in vivo


Junie Barbara Morquette

Institut et hôpital neurologiques de Montréal


Domaine : neurosciences, santé mentale et toxicomanies

Programme Formation postdoctorale - Citoyens canadiens et résidents permanents

Concours 2019-2020


Société canadienne de la sclérose en plaques

In Multiple Sclerosis (MS) immune cells and their by-product attach the myelin sheath leading to the degeneration of nerve fibers layers. This happens in the brain, the spinal cord and the optic nerve. The damage of nerve fibers is triggered by numerous harmful factors that engage diverse signalling cascades in neurons. To target the broad spectrum of signaling events that mediate nerve fibers damage in MS we have focused on non-coding small microRNAs (miRNA). miRNAs are epigenetic regulators of protein expression, targeting messenger RNAs. Dysregulation of miRNAs has been described in many neurodegenerative diseases including MS. In this study, we identified two miRNAs, miR-223-3p and miR-27a-3p, that were upregulated in neurons in a pre-clinical mouse model of MS (EAE) and in active MS lesions of human brains. Overexpression of miR-27a-3p or miR-223-3p protected dissociated cortical neurons from degeneration in an inflamed milieu.  Introduction of miR-223-3p in vivo in mouse retinal ganglion cells (RGCs) protected RGC axons from degeneration in the EAE model.  We identified that mRNAs in the glutamate receptor (GluR) pathway are enriched in miR-27a-3p and miR-223-3p targets. Antagonism of the GluR pathway protected neurons from PBMC-CM-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 excitotoxicity. We believe that our findings will shed light on the mechanisms underlying CNS degeneration and will lead to therapeutic tools to address neurological disabilities in MS.