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Regulation of neuronal plasticity by miRNAs: from physiology to pathology

This project is headed by Dr Alexandre Favereaux (Associate professor, biosketch) and currently involves María-José López-González (Post-doctoral fellow, biosketch) and Anaïs Soula (PhD student, biosketch).

MicroRNAs (miRNAs) are non-coding short hairpin RNAs ( 23nt) that modulate gene expression by inhibiting mRNA translation into proteins. The translation blockade can result from target mRNA degradation or transient confinement of mRNA in particles called Processing Bodies. A fundamental aspect of the miRNAs’ mechanism of action lies in the interaction with target mRNAs. Since full complementarity of miRNA to the target mRNA is not needed to induce silencing, a given miRNA can inhibit multiple targets. This multi-targeting property has been conserved through evolution since worms and can occur at the level of a pathway, where multiple proteins can be regulated by the same miRNA. This could be a crucial advantage if a given miRNA may regulate a function rather than the expression of a single gene, therefore lowering the energy cost of translational regulation.

MiRNAs is a widely express class of regulatory RNA in the brain, the main challenge being to pinpoint their roles and targets in specific neuronal functions. Recently, accruing evidence established miRNAs as essential regulators of proper neuronal function. In particular, it was demonstrated that miRNAs regulate many proteins involved in synaptic transmission and plasticity to sustain neuronal adaptation to network activity. Thus, miRNAs take part in the morphological and functional changes sustaining neuronal plasticity.

Our goal is to decipher the molecular mechanisms by which miRNAs regulate the synthesis of neuronal proteins in response to activity thus generating plasticity.
In particular, we investigate the role of miRNA regulation in both physiological and pathological maladaptive plasticity.

This project is subdivided in 3 axes:
1. The role of miRNAs in the homeostatic regulation of synaptic proteins in response to neuronal activity (in collaboration with O. Thoumine).
2. The role of miRNAs in the mechanisms of chronic pain such as neuropathic or cancer-associated pain and their analgesic potential (in collaboration with V. Heroguez and F. Viana).
3. The role of small vesicles containing miRNAs called exosomes that are released by neuronal cells and could play a crucial role in inter-neuronal communication (in collaboration with A. Trembleau and D. Perrais).

Technical approaches
- State-of-art biochemistry and cell biology
- RNA techniques : PCR, qRT-PCR, Next Generation Sequencing
- Bioinformatics


- Institut National du Cancer (2015-2018) “MicroRNAs: an innovative target for cancer patients suffering from severe pain” (coordinator).
- EU – FP7 (2013-2017) “Non-coding RNAs in neurogenic and neuropathic pain mechanisms and their application for risk assessment, patient stratification and personalised pain medicine”.
- IdEx University of Bordeaux (2013-2014) “miRNAs as diagnostic and prognostic markers in Amyotrophic Lateral Sclerosis” (coordinator).
- French Association for Research on Cancer (ARC, 2012-2014), “role of miRNAs in bone cancer pain mechanisms” (coordinator).
- National Agency for Research (ANR, 2011-2014), MirPain, miRNAs:new candidates to control chronic pain”.
- Ligue contre le cancer (2011-2012) “role of miRNAs in bone cancer pain mechanisms” (coordinator).
- Pharmaceutical company UPSA (2010-2011), “role of miRNAs in neuropathic pain mechanisms” (coordinator).

Selected publications

1- Letellier M, Elramah S, Mondin M, Soula A, Penn A, Choquet D, Landry M, Thoumine O, Favereaux A. miR-92a regulates expression of synaptic GluA1-containing AMPA receptors during homeostatic scaling. Nat Neurosci. 2014; 17(8):1040-2.
2- Elramah S, Landry M, Favereaux A. MicroRNAs regulate neuronal plasticity and are involved in pain mechanisms. Front Cell Neurosci. 2014; 8:31.
3- Kress M, Hüttenhofer A, Landry M, Kuner R, Favereaux A, Greenberg D, Bednarik J, Heppenstall P, Kronenberg F, Malcangio M, Rittner H, Uceyler N, Trajanoski Z, Mouritzen P, Birklein F, Sommer C, Soreq H. microRNAs in nociceptive circuits as predictors of future clinical applications. Front Mol Neurosci. 2013 Oct 17; 6:33.
4- Dolique T, Favereaux A, Roca-Lapirot O, Roques V, Léger C, Landry M & Nagy F. Unexpected association of the "inhibitory" neuroligin 2 with excitatory PSD95 in neuropathic pain. Pain. 2013; 154(11):2529-46.
5- Laffray S, Bouali-Benazzouz R, Papon MA, Favereaux A, Jiang Y, Holm T, Spriet C, Desbarats P, Fossat P, Le Feuvre Y, Decossas M, Héliot L, LANGEL U, Nagy F. Impairment of GABAB receptor dimer by endogenous 14-3-3ζ in chronic pain conditions. EMBO J. 2012; 31(15):3239-51.
6- Favereaux A, Thoumine O, Bouali-Benazzouz R, Roques V, Papon A, Abdel Salam S, Drutel G, Léger C, Calas A, Nagy F, Landry M. Bidirectional integrative regulation of Cav1.2 calcium channel by microRNA miR-103: role in pain. EMBO J. 2011; 30(18):3830-41.