Project: Investigating CK2-Mediated Phosphorylation of SYNGAP1 and Its Role in Neurodevelopmental Disorders

Principal Investigator: Heike Rebholz, PhD

Laboratory of Signaling Mechanisms in Neurological Disorders

Institut de Psychiatrie et Neuroscience de Paris (INSERM)

Co-funded by the CSNK2A1 Foundation and Syngap Research Fund (SRF)

Overview

This collaborative grant brings together two rare disease communities, Okur-Chung Neurodevelopmental Syndrome (OCNDS) and SYNGAP1-related disorders, to investigate a shared biological mechanism that could help explain overlapping symptoms such as seizures, learning difficulties, and autism spectrum features. The project focuses on CK2-mediated phosphorylation of SYNGAP1.

Scientific Background

SYNGAP1 is a critical postsynaptic protein that regulates neuronal signaling and plasticity. Its proper function depends on phosphorylation, a chemical “switch” that modifies how proteins behave. Dr. Rebholz’s team has discovered that phosphorylation of SYNGAP1 is markedly reduced in brain tissue from mouse models of OCNDS, where mutations in the CK2α subunit (CSNK2A1) lead to reduced kinase activity. By identifying how CK2 regulates SYNGAP1, this project aims to uncover a convergent mechanism between OCNDS and SYNGAP1 disorders, providing insight into why these syndromes share clinical features and pointing toward possible therapeutic strategies that could benefit multiple neurodevelopmental disorders.

Specific Aims

Aim 1: Identify phosphorylation sites. Determine which SYNGAP1 sites are directly phosphorylated by CK2 and whether OCNDS-linked CK2 variants impair this activity.

Aim 2: Define biological consequences. Examine how phosphorylation affects SYNGAP1 localization in neurons, its role in synaptic signaling, and regulation of Ras/Rap pathways.

Aim 3: Assess in vivo effects. Introduce phospho-mutant SYNGAP1 into wildtype mice to test impacts on seizures, repetitive behaviors, and memory.

Significance

By bridging two gene communities, this study embodies the Foundation’s mission to accelerate research and therapeutic development through collaboration. If CK2-mediated phosphorylation of SYNGAP1 proves to be a shared pathogenic mechanism, it could open the door to cross-disorder treatment strategies that target common pathways rather than individual genes.

Funding

This project is supported with a total of $160,000 in funding over two years (2025–2027), with 85% funding by SRF and 15% funding from CSNK2A1 Foundation.