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Physiological consequences of Protocadherin-10 sumoylation on neuronal function.

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 Unpublished data from my current lab identified a list of SUMO substrates at the synapse.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

Call for proposal

H2020-MSCA-IF-2018
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Coordinator

HUMANITAS MIRASOLE SPA
Address
Via Manzoni 56
20100 Rozzano (Mi)
Italy
Activity type
Private for-profit entities (excluding Higher or Secondary Education Establishments)
EU contribution
€ 171 473,28