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Reference : UMR7275-STEMAR1-003
Workplace : VALBONNE
Date of publication : Monday, April 19, 2021
Scientific Responsible name : Stéphane MARTIN
Type of Contract : PhD Student contract / Thesis offer
Contract Period : 36 months
Start date of the thesis : 27 September 2021
Proportion of work : Full time
Remuneration : 2 135,00 € gross monthly
Description of the thesis topic
Autism Spectrum Disorders (ASD) and Intellectual Disability (ID) affect millions of individuals worldwide and represent a major health and economic burden. Both disorders are characterized by compromised brain and cognitive functions and impaired social behaviours, representing a leading cause of handicap in children. Fragile X syndrome (FXS) is the most common inherited form of ID and the first-described monogenic cause of autism (1). This neurodevelopmental disorder results from mutations within the Fragile X Mental Retardation FMR1 gene leading to the lack of function of its protein product, the RNA-binding protein FMRP.
We recently demonstrated that FMRP is sumoylated in vivo and that its activity-dependent sumoylation is critical to the neuronal function (2). Sumoylation is the covalent conjugation of the Small Ubiquitin-like MOdifier (SUMO) protein to lysine residues of target proteins. It modulates the dynamics of multi-protein complexes by preventing and/or promoting protein-protein interactions, which is essential to establish a functional neuronal network (3).
Several FXS missense mutations lead to amino-acid changes that are close to the active SUMO sites of FMRP. This raises the exciting possibility that these mutations directly affect the regulation of FMRP sumoylation, impacting its function, and consequently leading to FXS. In the lab, we focused on the recurrent FXS R138Q mutation, which is located just 8 residues away from the main active sumoylation site of FMRP. We generated a Knock-in mouse model expressing the FXS R138Q mutation in FMRP (R138Q-KI) to study its pathophysiological impact. We measured an increase in the density of dendritic spines and critical alterations in the surface levels of glutamatergic AMPA receptors (AMPAR) leading to significant synaptic plasticity defects and to impaired cognitive and social behaviours (10). Therefore, the selected student will use state-of-the-art biochemical and cell-imaging techniques to unravel the molecular basis of these receptor trafficking defects. To achieve this aim, the PhD student will work on two complementary tasks to:
1- Characterize the activity-dependent AMPA receptor trafficking defects in R138Q-KI neurons.
2- Explore the efficacy of pharmacological drugs to restore the AMPA receptor trafficking defects in R138Q-KI neurons.
This project is completely innovative and we are uniquely placed to undertake the work proposed since we have a clear expertise in receptor trafficking (4-6), cell imaging (2, 6-10) and have a unique access to the FXS KI model.
Publications related to the project:
1- Darnell J et al. Nature Neuroscience 16:1530 (2013).
2- Khayachi A., Gwizdek C., et al. Nature Communications 9:757 (2018).
3- Schorova L. & Martin S. Frontiers in Synaptic Neuroscience 8:9 (2016).
4- Martin S et al. Embo Journal 23:4749 (2004)
5- Martin S et al. Nature 447:321 (2007)
6- Martin S et al. J Biol Chem 283:36435 (2008)
7- Cassé F. & Martin S. Frontiers in Cell Neuroscience 9:367 (2015).
8- Loriol C. et al. Nature Communications 5:5113 (2014).
9- Schorova L. et al. Cellular & Molecular Life Sciences 76:3019 (2019).
10- Prieto M., Folci A., et al. Nature Communications 12:1557 (2021).
Founded in 1989, the IPMC is a multi-thematic research center in biology at the CNRS and the Université Côte d'Azur (UCA). It benefits from its location on the exceptional site of Sophia Antipolis, Europe's leading technology park: 2,500 companies, 10,000 students and researchers, and the presence of the main French research institutions in the field of biological sciences.
The 20 international research teams take advantage of state-of-the-art equipment and high level of expertise in molecular & cellular biology, imaging, cytometry, electrophysiology, functional genomics and integrative biology.
Constraints and risks
There are no constraints.
Biological and chemical risks.
Thesis funded via an 'Agence Nationale de la Recherche' program grant.
Candidates must join their CV and the name and contact information of two references.
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