Lejeune FOLCI 2021 - Investigating the functional consequences of Oligophrenin-1 sumoylation in X-Linked Intellectual Disability (DSB.AD004.362)

Thematic area

Biomedical sciences

Project area

Structure responsible for the research project

Institute of neuroscience (IN)

Project manager

ALESSANDRA FOLCI
Phone number: 0282245254
Email: alessandra.folci@in.cnr.it

Abstract

Intellectual disability (ID) affects millions of individuals worldwide and represents a major health and economic burden in the modern society. Understanding the molecular mechanisms underlying ID is essential to develop novel therapeutic approaches. Mutations in Ophn1 gene cause the loss of function of Oligophrenin-1 protein (OPHN1) protein, leading to syndromic ID characterized by cerebellum abnormalities. OPHN1 is a Rho-GAP protein that negatively regulates the activity of RhoA in neurons. Loss of OPHN1 affects both spine density and morphology and impairs functional changes occurring upon synaptic plasticity. Conversely, overexpression of exogenous OPHN1 promotes AMPA receptor (AMPAR) stabilization at the surface by altering its endocytosis properties. Given the importance of such processes, a tight regulation of OPHN1 activity is critical to proper synaptic transmission and plasticity. Our preliminary data strongly demonstrate for the first time that OPHN1 is targeted by sumoylation. Sumoylation is an essential post-translational modification (PTM) that controls several cellular processes, including postsynaptic differentiation and spine elimination. Bioinformatics analysis on

Goals

In order to unravel the physiological and pathological consequences of OPHN1 sumoylation, we propose the following aims. Aim1: Assessing the functional consequences of OPHN1 sumoylation in neurons. In neurons, OPHN1 function is modulated in an activity-dependent manner and is critical for neuronal architecture and synaptic strength regulation. Here, we will compare the effect of the wild-type (WT) and non-sumoylatable forms of OPHN1 on spine architecture and AMPAR trafficking. The non-sumoylatable form of OPHN1 will be generated by mutating the K403 into Arginine (K403R). Then, we will virally introduce either this mutant or the WT form in OPHN1 KO neurons and compare the effects on synapse development and maturation, spine structure and AMPAR trafficking and transmission. To this end we will combine sophisticated biochemical approaches with advanced live imaging techniques that I mastered during my postdocs abroad. Aim2: Investigating the link between OPHN1 ID-related mutation and altered OPHN1 sumoylation. First, we will assess the pathological consequences of OPHN1 sumoylation by analyzing the effect of the G412D mutation on excitatory synapse development and function using the

Start date of activity

01/10/2021

Keywords

sumoylation, oligophrenin-1, intellectual disability

Last update: 19/04/2025