SUMO-PCDH10 · Physiological consequences of Protocadherin-10 sumoylation on neuronal function.
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2019-06-01 → 2021-08-31
- EU contribution
- €171,473
- Participants
- 1
- Scheme
- MSCA-IF-EF-SE
Lines connect the coordinator with its partners.
Results in brief
Physiological consequences of Protocadherin-10 sumoylation on neuronal function.
Synapses are the basic functional units of the central nervous system (CNS) where the neuronal transmission takes place. Dendritic spines, representing the postsynaptic compartment of excitatory synapses, are small membrane protrusions enriched in actin. Synapse physiology and maturation is regulated by the orchestrated activity of plenty of proteins, including enzymes, receptors, scaffolding and cell adhesion molecules (CAM). Protocadherin-10 (Pcdh10) is a synaptic CAM highly expressed in the CNS, both in the pre- and post-synaptic compartments. At the molecular level, Pcdh10 targets the postsynaptic scaffolding protein PSD-95, in its ubiquitinated form, to the proteasome and promotes synaptic elimination. Interestingly, an altered copy number of the Pcdh10 gene associates with the development of Autism Spectrum Disorder (ASD) in humans. Accordingly, mice lacking one copy of Pcdh10 (Pcdh10+/-) display a severe impairment in social behaviors. However, the molecular mechanisms by which Pcdh10 function impacts synapse assembly and stability are still unclear. Our preliminary data identified Pcdh10 as a potential target of sumoylation. Sumoylation is an essential post-translational modification critical to several cellular signaling pathways. It consists in the covalent but reversible enzymatic conjugation of the Small Ubiquitin-like MOdifier (SUMO) protein to specific lysine residues of substrate proteins. In neurons, sumoylation plays a key role in controlling several neuronal functions including presynaptic release and dendritic spine maturation. Here, we hypothesize that sumoylation of Pcdh10 is crucial for synapse maturation. Thus, the overall goal of my research project is to unveil the physiopathological consequences of Pcdh10 sumoylation in neurons.
Data: CORDIS, © European Union
Project 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 Unpublished data from my current lab identified a list of SUMO substrates at the synapse.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.
Original text from CORDIS.
Participants
- HUMANITAS MIRASOLE SPA · Rozzano (Mi)CoordinatorItaly
Links
Data: CORDIS, © European Union