Impaired dopaminergic neuronal differentiation in GBA associated Parkinson’s disease midbrain organoids is accompanied by an increased progenitor pool in cell cycle arrest#

Authors#

Isabel Rosety, Alise Zagare, Claudia Saraiva, Sarah Nickels, Paul Antony, Catarina Almeida, Enrico Glaab, Rashi Halder, Sergiy Velychko, Thomas Rauen, Hans R. Schoeler, Silvia Bolognin, Thomas Sauter, Javier Jarazo, Rejko Krüger, Jens Christian Schwamborn

Abstract#

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 a decrease in the number and complexity of dopaminergic neurons. This was accompanied by an increase in the neural progenitor population showing signs of oxidative stress-induced damage and premature cellular senescence. These results provide insights into how GBA mutations may lead to neurodevelopmental defects thereby predisposing to PD pathology.