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Thèse Sara Elramah

Towards a better understanding of microRNA function in neuronal plasticity: implications in synaptic homeostasis and maladaptive plasticity in bone cancer conditions.

Le 22 novembre 2013

Sara Elramah,  lieu de thèse Institut François Magendie 14h. Directeur de thèse  Alexandre Favereaux , laboratoire de Marc Landry. Institut: IINS


MicroRNAs (miRNAs) are a type of small RNA molecules (21-25nt), with a central role in RNA silencing and interference. MiRNAs function as negative regulators of gene expression at the post-transcriptional level, by binding to specific sites on their targeted mRNAs.
A process results in mRNA degradation or repression of productive translation. Because partial binding to target mRNA is enough to induce silencing, each miRNA has up to hundreds of targets. miRNAs have been shown to be involved in most, if not all, fundamental biological processes. Some of the most interesting examples of miRNA activity regulation are coming from neurons. Almost 50% of all identified miRNAs are expressed in the mammalian brain. Furthermore, miRNAs appear to be differentially distributed in distinct brain regions and neuron types. Importantly, miRNAs are reported to be differentially distributed at the sub-cellular level. Recently, miRNAs have been suggested to be involved in the local translation of neuronal compartments. This has been derived from the observations reporting the presence of miRNAs and the protein complexes involved in miRNA biogenesis and function in neuronal soma, dendrites, and axons. Deregulation of miRNAs has been shown to be implicated in pathological conditions. The present thesis aimed at deciphering the role of miRNA regulation in neuronal plasticity. Here we investigated the involvement of miRNA in synaptic plasticity, specifically in homeostatic synaptic plasticity mode. In addition, we investigated the involvement of miRNAs in the maladaptive nervous system state, specifically, in bone cancer pain condition.

We hypothesized that local regulation of AMPA receptor translation in dendrites upon homeostatic synaptic scaling may involve miRNAs. Using bioinformatics, qRT-PCR and luciferase reporter assays, we identified several brain-specific miRNAs including miR-92a, targeting the 3’UTR of GluA1 mRNA. Immunostaining of AMPA receptors and recordings of miniature AMPA currents in primary neurons showed that miR-92a selectively regulates the synaptic incorporation of new GluA1-containing AMPA receptors during activity blockade.

Pain is a very common symptom associated with cancer and is still a challenge for clinicians due to the lack of specific and effective treatments. This reflects the crucial lack of knowledge regarding the molecular mechanisms responsible for cancer-related pain. Combining miRNA and mRNA screenings we were able to identify a regulatory pathway involving the nervous system-enriched miRNA, miR-124. Thus, miR-124 downregulation was associated with an upregulation of its predicted targets, Calpain 1, Synaptopodin and Tropomyosin 4 in a cancer-pain model in mice. All these targets have been previously identified as key proteins for the synapse function and plasticity. Clinical pertinence of this finding was assessed by the screening of cerebrospinal fluid from cancer patient suffering from pain who presented also a downregulation of miR-124, strongly suggesting miR-124 as a therapeutic target. In vitro experiments confirmed that miR-124 exerts a multi-target inhibition on Calpain 1, Synaptopodin and Tropomyosin 4. In addition, intrathecal injection of miR-124 was able to normalize the Synaptopodin expression and to alleviate the initial phase of cancer pain in mice

Jury

President
Martin Teichmann
Professor Université Bordeaux Segalen. Institut Européen de Chimie et Biologie (IECB) INSERM U869


Rapporteurs
Marzia Malcangio
King's College London

Alain Trembleau
Prof.- Université Pierre et Marie Curie


Examinateurs
Valérie Fénelon
Professeur des Universités - PhD UFR Sciences biologiques U Bx1 ; Université Bordeaux 1
Florence Rage
Chargé de recherche CNRS IGMM (Institut de Génétique Moléculaire de Montpellier) Montpellier

Directeur de thèse



Alexandre Favereaux
PhD
Associate Professor
University of Bordeaux
Interdisciplinary Institute for NeuroScience - UMR 5297
Central mechanisms of pain sensitization
146, rue Léo Saignat, 33 077 Bordeaux Cedex, France

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