Cell cycle arrest of neural progenitors causes impaired dopaminergic neuronal differentiation in GBA associated Parkinson’s disease midbrain organoids [1]

The mechanisms underlying Parkinson's disease (PD) etiology are only partially understood despite intensive research conducted in the field. Recent evidence suggests that early neurodevelopmental defects might play a role in cellular susceptibility to neurodegeneration. To study the early developmental contribution of GBA mutations in PD we used patient-derived iPSCs carrying a heterozygous N370S mutation in the GBA gene. Patient-specific midbrain organoids displayed GBA-PD relevant phenotypes such as reduction of GCase activity, autophagy impairment and mitochondrial dysfunction. Genome-scale metabolic (GEM) modeling predicted changes in lipid metabolism which were validated with lipidomics analysis, showing significant differences in the lipidome of GBA-PD. In addition, patient-specific midbrain organoids exhibited an increase in the neural progenitor population showing signs of cellular senescence. This was accompanied by a decrease in the number and complexity of dopaminergic neurons. These results provide insights into how GBA mutations may lead to neurodevelopmental defects thereby predisposing to PD pathology. Comparative gene expression profiling analysis of RNA-seq data from GBA-PD patient-derived organoids and control organoids