Impaired neuron differentiation in GBA-associated Parkinson's disease is linked to cell cycle defects in organoids.
NPJ Parkinsons Dis
; 9(1): 166, 2023 Dec 18.
Article
in En
| MEDLINE
| ID: mdl-38110400
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Language:
En
Journal:
NPJ Parkinsons Dis
Year:
2023
Document type:
Article
Affiliation country:
Luxembourg
Country of publication:
United States