TY - JOUR
KW - Cellular neuroscience
KW - Neural Stem Cells
KW - Parkinson's disease
AU - Isabel Rosety
AU - Alise Zagare
AU - Claudia Saraiva
AU - Sarah Nickels
AU - Paul Antony
AU - Catarina Almeida
AU - Enrico Glaab
AU - Rashi Halder
AU - Sergiy Velychko
AU - Thomas Rauen
AU - Hans R. Schöler
AU - Silvia Bolognin
AU - Thomas Sauter
AU - Javier Jarazo
AU - Rejko Krüger
AU - Jens C. Schwamborn
AB - 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.
BT - npj Parkinson's Disease
DA - 2023-12-18
DO - 10.1038/s41531-023-00616-8
LA - en
N2 - 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.
PY - 2023
EP - 166
T2 - npj Parkinson's Disease
TI - Impaired neuron differentiation in GBA-associated Parkinson’s disease is linked to cell cycle defects in organoids
UR - https://www.nature.com/articles/s41531-023-00616-8
VL - 9
Y2 - 2024-08-13
SN - 2373-8057
ER -