Impaired neuron differentiation in GBA-associated Parkinson's disease is linked to cell cycle defects in organoids.

Autor: Rosety I; Developmental and Cellular Biology, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, Luxembourg.; OrganoTherapeutics SARL-S, Esch-sur-Alzette, Luxembourg., Zagare A; Developmental and Cellular Biology, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, Luxembourg., Saraiva C; Developmental and Cellular Biology, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, Luxembourg., Nickels S; Developmental and Cellular Biology, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, Luxembourg., Antony P; Translational Neuroscience, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg., Almeida C; Developmental and Cellular Biology, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, Luxembourg., Glaab E; Biomedical Data Science group, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg., Halder R; Systems Ecology Group, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg., Velychko S; Max Planck Institute for Molecular Biomedicine, MPG White Paper Group - Animal Testing in the Max Planck Society, Muenster, Germany., Rauen T; Max Planck Institute for Molecular Biomedicine, MPG White Paper Group - Animal Testing in the Max Planck Society, Muenster, Germany., Schöler HR; Max Planck Institute for Molecular Biomedicine, MPG White Paper Group - Animal Testing in the Max Planck Society, Muenster, Germany., Bolognin S; Developmental and Cellular Biology, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, Luxembourg., Sauter T; Department of Life Sciences and Medicine, University of Luxembourg, Belvaux, 4367, Luxembourg., Jarazo J; Developmental and Cellular Biology, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, Luxembourg.; OrganoTherapeutics SARL-S, Esch-sur-Alzette, Luxembourg., Krüger R; Translational Neuroscience, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg.; Transversial Translational Medicine, Luxembourg Institute of Health (LIH), 1 A-B rue Thomas Ediison, L-1445, Strassen, Luxembourg., Schwamborn JC; Developmental and Cellular Biology, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, Luxembourg. jens.schwamborn@uni.lu.
Jazyk: angličtina
Zdroj: NPJ Parkinson's disease [NPJ Parkinsons Dis] 2023 Dec 18; Vol. 9 (1), pp. 166. Date of Electronic Publication: 2023 Dec 18.
DOI: 10.1038/s41531-023-00616-8
Abstrakt: 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.
(© 2023. The Author(s).)
Databáze: MEDLINE
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