02195nas a2200373   4500000000100000000000100001008004100002260001500043653002600058653002200084653002400106100001800130700001700148700002000165700001800185700001600203700002100219700001700240700001700257700002000274700001700294700002100311700002000332700001800352700001800370700001800388700002300406245012100429856005500550300000800605490000600613520118800619022001401807       2023                            d  c2023-12-1810aCellular neuroscience10aNeural Stem Cells10aParkinson's disease1 aIsabel Rosety1 aAlise Zagare1 aClaudia Saraiva1 aSarah Nickels1 aPaul Antony1 aCatarina Almeida1 aEnrico Glaab1 aRashi Halder1 aSergiy Velychko1 aThomas Rauen1 aHans R. Schöler1 aSilvia Bolognin1 aThomas Sauter1 aJavier Jarazo1 aRejko Krüger1 aJens C. Schwamborn00aImpaired neuron differentiation in GBA-associated Parkinson’s disease is linked to cell cycle defects in organoids  uhttps://www.nature.com/articles/s41531-023-00616-8  a1660 v93 aThe 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.  a2373-8057