BRAIN ORGANOIDS AND NEURONAL MODELS TO UNDERSTAND SCHAAF-YANG SYNDROME

Schaaf-Yang Syndrome (SYS) is an ultra-rare neurodevelopmental disorder caused by truncating mutations in the paternal allele of MAGEL2, a gene within the 15q11-q13 imprinted region. Heterologous expression studies have shown that truncating mutations lead to the expression of a shorter, stable protein that mislocalizes to the nucleus instead of the cytoplasm.
Using patient-derived and control iPSCs, we have validated the use of β-amyloid 1-40 secretion as a biomarker for MAGEL2 dysfunction, and studied global expression pattern changes in iNeurons, iAstrocytes and brain organoids, compared neural development in dorsal and ventral cortical organoids, and evaluated possible functional defects by calcium imaging analysis.
MAGEL2 shows a very early peak of expression in both dorsal and ventral organoids, with a sharp descent between 45 and 60 days of culture. A combined analysis of all data points identified 155 significant differentially expressed genes (DEGs) in organoids expressing a truncated MAGEL2, while individual timepoint analyses highlight a higher number of DEGs in early timepoints and subpallial organoids. Several of the disregulated genes involve zinc finger proteins and other regulatory genes.
In addition, significant functional differences can be observed: patient-derived neuronal models show impaired neuronal migration, while calcium imaging results support an impaired maturation and function of inhibitory signalling.
Together, these findings reveal shared molecular changes across different cell types, and identify neurodevelopmental defects that may affect early brain development in patients. In addition, our results provide biomarkers and cellular and functional models that may be used in future therapeutic research.