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CORDIS

Physiological consequences of Protocadherin-10 sumoylation on neuronal function.

Project description

Molecular insight into synapse elimination

Synapses are the main neurological structures responsible for the formation of neural circuits and the transmission of information between neurons. Under physiological conditions, the formation and elimination of synapses supports neuronal plasticity. The EU-funded SUMO-PCDH10 project aims to dissect the mechanism of synapse elimination and identify the key determinants. Researchers will focus on protocadherin-10 (PCDH10), an autism-related cell adhesion transmembrane protein known to regulate synapse density and function. They will investigate how a specific post-translational modification known as sumoylation is responsible for PCDH10 function. Given that several neurodevelopmental disorders are associated with synapse elimination, results will have profound clinical consequences.

Objective

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 Unpublished data from my current lab identified a list of SUMO substrates at the synapse.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.

Coordinator

HUMANITAS MIRASOLE SPA
Net EU contribution
€ 171 473,28
Address
VIA MANZONI 56
20100 Rozzano (Mi)
Italy

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Region
Nord-Ovest Lombardia Milano
Activity type
Private for-profit entities (excluding Higher or Secondary Education Establishments)
Links
Total cost
€ 171 473,28