JCJC SVSE 4 - JCJC - SVSE 4 - Neurosciences

Physiological Consequences of Fragile X Mental Retardation Protein Sumoylation – SUMO-ID

Role of protein modifications in intellectual disability

Alteration of protein modification in nerve cells may lead to developmental defects and therefore to intellectual disabilities.

Understand the physiological functions of protein modification in the brain

The brain allows you to think, learn and remember. It contains about 100 billion nerve cells called neurons, each having 10,000 connections to other neurons. These connections, called synapses, chemically transmit the information that controls all brain function. These highly regulated processes also named synaptic transmission are believed to be the basis of learning and memory. A major feature of a healthy brain is that synapses can modify how efficiently they work, by increasing or decreasing the amount of information transmitted. We discovered that a small protein called SUMO can help to regulate the way brain cells communicate between each others. Interestingly, we also found that SUMO can conjugate to a molecule that is responsible for an inherited cause of mental impairment. In this work, we investigate by which mechanisms this small SUMO molecule regulates the flow of transmitted information between nerve cells.

This research will help to understand how neurons communicate and may provide insights into the causes of brain diseases that have been linked to incorrect neuronal communication.

Our data indicate that modification of proteins by the small molecule SUMO is essential to control nerve cell architecture and subsequently the communication between these cells.

In the future, our work will help to understand how neurons communicate and how protein modifications regulate the fate of neuronal molecules in the brain. Therefore we are confident that we can make real and meaningful advances in this competitive field of brain science. We therefore believe that this work will inform on strategies that may provide tractable targets for therapeutic intervention.

A publication in 'Biol Cell' shows how protein modifications in neuronal cells are regulated by cell activity.

Mental Retardation (MR) is the most common cause of children heavy handicap and represents a major social and economical problem. Fragile X Syndrome (FXS) is the most frequent inherited cause of Intellectual Disability (ID) in children. It results from the transcriptional silencing of the Fragile X Mental Retardation 1 gene and consequently to the loss of function of its product, the Fragile X Mental Retardation Protein (FMRP). The absence of FMRP in neurones leads to an abnormal immature neuronal morphology with increased spine length and density. FMRP is therefore playing a central role both in neuronal development and synaptic plasticity. FMRP is a mobile RNA binding protein that participates in the transport of specific target mRNAs and their local translation. However, the molecular mechanisms underlying the physiological regulation of FMRP-mediated mRNA trafficking, translation and subsequent protein synthesis are still largely unknown. We report in this grant application that FMRP is sumoylated in vivo. Sumoylation is a post-translational modification that consists in the covalent enzymatic conjugation of the protein SUMO (Small Ubiquitin-like MOdifier) to specific lysine residues of substrate proteins. Sumoylation was originally thought to target nuclear proteins but it has become clear that it also has important extranuclear roles and regulates the function of many proteins including several key molecules involved in neurological disorders (for a review, see Martin et al., 2007, Nature Reviews Neuroscience). Our project aims at understanding the functional consequences of FMRP sumoylation in the brain.

The work proposed in this application is completely innovative and of fundamental importance to understand the physiological roles of FMRP. These data will also represent the basis for future studies aiming at understanding the roles played by sumoylation in other neurological disorders. I believe that my young independent research group is uniquely placed to undertake the experiments proposed in this application. Indeed, we have a unique expertise in synaptic sumoylation and a wealth of preliminary results demonstrating the feasibility of the work proposed. Furthermore, we have established expert collaborations and I therefore believe that if this work is funded, it will inform on strategies that may provide tractable targets for therapeutic intervention.

Project coordinator


The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.



Help of the ANR 338,578 euros
Beginning and duration of the scientific project: July 2011 - 48 Months

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