@article{4211,
  keywords = {Cellular neuroscience, Neural Stem Cells, Parkinson's disease},
  author = {Isabel Rosety and Alise Zagare and Claudia Saraiva and Sarah Nickels and Paul Antony and Catarina Almeida and Enrico Glaab and Rashi Halder and Sergiy Velychko and Thomas Rauen and Hans R. Schöler and Silvia Bolognin and Thomas Sauter and Javier Jarazo and Rejko Krüger and Jens C. Schwamborn},
  title = {Impaired neuron differentiation in GBA-associated Parkinson’s disease is linked to cell cycle defects in organoids},
  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.},
  year = {2023},
  journal = {npj Parkinson's Disease},
  volume = {9},
  pages = {166},
  month = {2023-12-18},
  issn = {2373-8057},
  url = {https://www.nature.com/articles/s41531-023-00616-8},
  doi = {10.1038/s41531-023-00616-8},
  language = {en},
}