Neurology; Neurology (clinical); Cellular and Molecular Neuroscience
Abstract :
[en] 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.
Research center :
Luxembourg Centre for Systems Biomedicine (LCSB): Developmental and Cellular Biology (Schwamborn Group) Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) Luxembourg Centre for Systems Biomedicine (LCSB): Biomedical Data Science (Glaab Group)
Disciplines :
Neurology Life sciences: Multidisciplinary, general & others
Author, co-author :
Rosety, Isabel ; 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, Alise; Developmental and Cellular Biology, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, Luxembourg
Saraiva, Claudia ; Developmental and Cellular Biology, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, Luxembourg
Nickels, Sarah; Developmental and Cellular Biology, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, Luxembourg
Antony, Paul; Translational Neuroscience, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
Almeida, Catarina ; Developmental and Cellular Biology, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, Luxembourg
Halder, Rashi; Systems Ecology Group, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
Velychko, Sergiy; Max Planck Institute for Molecular Biomedicine, MPG White Paper Group - Animal Testing in the Max Planck Society, Muenster, Germany
Rauen, Thomas ; Max Planck Institute for Molecular Biomedicine, MPG White Paper Group - Animal Testing in the Max Planck Society, Muenster, Germany
Schöler, Hans R; Max Planck Institute for Molecular Biomedicine, MPG White Paper Group - Animal Testing in the Max Planck Society, Muenster, Germany
Bolognin, Silvia; Developmental and Cellular Biology, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, Luxembourg
Sauter, Thomas; Department of Life Sciences and Medicine, University of Luxembourg, Belvaux, 4367, Luxembourg
Jarazo, Javier ; 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, Rejko ; 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, Jens C ; Developmental and Cellular Biology, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, Luxembourg. jens.schwamborn@uni.lu
We thank Dr. Nico J. Diederich and Laura Longhino from Centre Hospitalier de Luxembourg, Dr. Anna-Lena Hallmann from the Max Planck Institute, Anthony Schapira, David Chau and Revital Golan from University College London, StemBANCC and the Coriell Institute for providing cell lines. Dr. Anna Monzel for iPSC characterization and Michele Bassis for technical assistance. Microscopy and flow cytometry were supported by the LCSB bio-imaging platform. We thank the Disease Modeling Screening Platform from LCSB and LIH for their help with performing automated and high-throughput procedures. We also thank the private donors who support our work at the Luxembourg Center for Systems Biomedicine. This work leading to this manuscript was supported by the following funding: Fonds National de la Recherche (FNR) Luxembourg AFR program; Fonds National de la Recherche (FNR) Luxembourg INTER/JPND/15/11092422; Fonds National de la Recherche (FNR) Luxembourg, National Centre of Excellence in Research on Parkinson’s Disease (NCER-PD) FNR/NCER13/BM/11264123; National Institutes of Health grant U12AV123456; National Institutes of Health grant R01AB123456; William K. Bowes Jr Foundation; German Research Foundation grant AB 1234/1-1; Max Planck Society’s White Paper-Project: Brain Organoids: Alternatives to Animal Testing in Neuroscience; Office of Biological and Environmental Research of the U.S. Department of Energy Atmospheric System Research Program Interagency Agreement grant DE-SC0000001; National Institute of Health Research UK.We thank Dr. Nico J. Diederich and Laura Longhino from Centre Hospitalier de Luxembourg, Dr. Anna-Lena Hallmann from the Max Planck Institute, Anthony Schapira, David Chau and Revital Golan from University College London, StemBANCC and the Coriell Institute for providing cell lines. Dr. Anna Monzel for iPSC characterization and Michele Bassis for technical assistance. Microscopy and flow cytometry were supported by the LCSB bio-imaging platform. We thank the Disease Modeling Screening Platform from LCSB and LIH for their help with performing automated and high-throughput procedures. We also thank the private donors who support our work at the Luxembourg Center for Systems Biomedicine. This work leading to this manuscript was supported by the following funding: Fonds National de la Recherche (FNR) Luxembourg AFR program; Fonds National de la Recherche (FNR) Luxembourg INTER/JPND/15/11092422; Fonds National de la Recherche (FNR) Luxembourg, National Centre of Excellence in Research on Parkinson’s Disease (NCER-PD) FNR/NCER13/BM/11264123; National Institutes of Health grant U12AV123456; National Institutes of Health grant R01AB123456; William K. Bowes Jr Foundation; German Research Foundation grant AB 1234/1-1; Max Planck Society’s White Paper-Project: Brain Organoids: Alternatives to Animal Testing in Neuroscience; Office of Biological and Environmental Research of the U.S. Department of Energy Atmospheric System Research Program Interagency Agreement grant DE-SC0000001; National Institute of Health Research UK.
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