Midbrain organoids to investigate the cause of Parkinson's disease
December 2023
University of Luxembourg, Esch-sur-Alzette, Luxembourg
The mechanisms underlying the aetiology of Parkinson's disease are still only partially understood. Recent evidence suggests that early defects in neurodevelopment may play a role in cellular susceptibility to neurodegeneration. To investigate the early developmental contribution of GBA mutations in Parkinson's patients, iPSCs carrying a heterozygous N370S mutation in the GBA gene were used. Patient-specific midbrain organoids exhibited GBA-PD-related phenotypes, such as a reduction in GCase activity, impaired autophagy and mitochondrial dysfunction. Genome-scale metabolic modelling (GEM) predicted changes in lipid metabolism, which were validated by lipidome analysis and showed significant differences in the lipidome of GBA-PD. In addition, patient-specific midbrain organoids showed a decrease in the number and complexity of dopaminergic neurons. This was accompanied by an increase in the neural progenitor population, which showed signs of oxidative stress-induced damage and premature cellular senescence. These results shed light on how GBA mutations can lead to neurodevelopmental defects and thus favour the development of Parkinson's disease.
Impaired neuron differentiation in GBA-associated Parkinson’s disease is linked to cell cycle defects in organoids
Jens C. Schwamborn
Added on: 02-19-2024
[1] https://www.nature.com/articles/s41531-023-00616-8?emci=89763c75-30c5-ee11-b660-002248223197&emdi=f00becb3-e2c5-ee11-b660-002248223848&ceid=2015591#Sec10
