Description du projet
Aperçu moléculaire de l’élimination des synapses
Les synapses sont les principales structures neurologiques responsables de la formation des circuits neuronaux et de la transmission des informations entre les neurones. En conditions physiologiques, la formation et l’élimination des synapses favorisent la plasticité neuronale. Le projet SUMO-PCDH10, financé par l’UE, a pour ambition de disséquer le mécanisme d’élimination des synapses et d’en identifier les déterminants essentiels. Les chercheurs se concentreront sur la protocadhérine-10 (PCDH10), une protéine transmembranaire d’adhésion cellulaire liée à l’autisme et connue pour réguler la densité et la fonction des synapses. Ils étudieront comment une modification post-traductionnelle spécifique, appelée sumoylation, est responsable de la fonction de la PCDH10. Plusieurs troubles du développement neurologique étant associés à l’élimination des synapses, les résultats auront de profondes conséquences cliniques.
Objectif
Sumoylation is an essential post-translational modification that regulates a wide range of cellular functions. Interestingly, several proteins involved in synaptic functions have been shown to be SUMO targets. Unpublished data from my current lab identified a list of SUMO substrates at the synapse. Among them, we find Protocadherin-10 (PCDH10), an autism-related cell adhesion transmembrane protein. Mice lacking one copy of Pcdh10 gene present abnormal spine density and morphology, reduced expression of NMDA receptors in the amygdala and sociability deficits. Furthermore, PCDH10 recruits ubiquitinated PSD-95 to the proteasome and promotes synapse elimination. These findings demonstrate that PCDH10 is centrally involved in the regulation of synapse density and function. However, whether the sumoylation of PCDH10 plays a role in this process remains to be elucidated. Thus, I performed a bioinformatic analysis showing that the lysine 831 (K831) of PCDH10 has a high SUMO predictive value. Interestingly, the K831 is located in the proteosomal interacting region (PIR), which is critical to allow PSD-95 degradation and, consequently, synapse elimination. Sumoylation regulates protein-protein interactions by providing novel docking sites or promoting the dissociation of the binding. Therefore, I hypothesize that sumoylation of PCDH10 is crucial for synapse elimination by regulating the interaction with the proteasome. Thus, the overall goal of my research project is to unveil the physiopathological consequences of PCDH10 sumoylation in neurons. Since synapse elimination is impaired in several neurodevelopmental disorders, I am confident that the data arising from this work will provide groundbreaking knowledge in the understanding of the molecular mechanisms underlying ID in patients carrying Pcdh10 mutations. Furthermore, uncovering the impact of sumoylation on the development of mental disorders will open up a thrilling topic in the neuroscience field.
Champ scientifique
Programme(s)
Régime de financement
MSCA-IF-EF-SE - Society and Enterprise panelCoordinateur
20100 Rozzano (Mi)
Italie