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Cell cycle arrest of neural progenitors causes impaired dopaminergic neuronal differentiation in GBA associated Parkinson’s disease midbrain organoids [1]

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

ORGANISM(S): Homo sapiens

PROVIDER: GSE208781 | GEO | 2022/07/24

REPOSITORIES: GEO

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Cell cycle arrest of neural progenitors causes impaired dopaminergic neuronal differentiation in GBA associated Parkinson’s disease midbrain organoids [2]

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