Identifying disease-critical cell types and pathways to guide new treatment approaches for Houge-Janssens syndrome type 2 (HJS2)

De novo mutations in PPP2R1A, encoding the scaffolding Aα subunit of Protein Phosphatase 2A (PP2A), are causes of Houge-Janssens syndrome type 2 (HJS2), characterized by neurodevelopmental delay, intellectual disability and other symptoms such as epilepsy. Although biochemical characterization of PPP2R1A variants demonstrated their loss-of-function, insights into the pathogenic mechanisms in brain are still lacking. We created and studied the behavior of heterozygous Ppp2r1a M180T/+ and R182W/+ knockin mice, showing that they mimic both distinct patient groups of HJS2. Preliminary results in brain organoids emphasize the early developmental defects caused by the variants, culminating in misbalanced neurogenesis by affecting neuronal cell signaling. In this project, we aim to dissect the role of PP2A during early brain development in HJS2 severity groups by combining cutting-edge technologies for the cellular, molecular and functional characterization of 2D human stem cell and 3D brain organoid models of HJS2, thereby identifying molecular targets to evaluate treatment approaches. Furthermore, we will examine cross-species validation of these mechanisms in mouse embryonic brain cortex. The integration of proposed in vitro and in vivo studies will provide missing insights into the disease mechanisms of HJS2 and, foremost, enable suggesting and preclinical testing of the first therapeutic strategies.