NAD; Humans; NAD/metabolism; Mitochondria/metabolism; Dopaminergic Neurons/metabolism; Parkinson Disease/metabolism; Neural Stem Cells/metabolism; Medicine (miscellaneous); Biochemistry, Genetics and Molecular Biology (all); Agricultural and Biological Sciences (all); General Agricultural and Biological Sciences; General Biochemistry, Genetics and Molecular Biology
Abstract :
[en] The vast majority of Parkinson's disease cases are idiopathic. Unclear etiology and multifactorial nature complicate the comprehension of disease pathogenesis. Identification of early transcriptomic and metabolic alterations consistent across different idiopathic Parkinson's disease (IPD) patients might reveal the potential basis of increased dopaminergic neuron vulnerability and primary disease mechanisms. In this study, we combine systems biology and data integration approaches to identify differences in transcriptomic and metabolic signatures between IPD patient and healthy individual-derived midbrain neural precursor cells. Characterization of gene expression and metabolic modeling reveal pyruvate, several amino acid and lipid metabolism as the most dysregulated metabolic pathways in IPD neural precursors. Furthermore, we show that IPD neural precursors endure mitochondrial metabolism impairment and a reduced total NAD pool. Accordingly, we show that treatment with NAD precursors increases ATP yield hence demonstrating a potential to rescue early IPD-associated metabolic changes.
Disciplines :
Life sciences: Multidisciplinary, general & others
Author, co-author :
ZAGARE, Alise ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Developmental and Cellular Biology
Preciat, German; Metabolomics and Analytics Center, Leiden Academic Centre for Drug Research, Leiden University, 2300 RA, Leiden, The Netherlands
NICKELS, Sarah Louise ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Developmental and Cellular Biology
Luo, Xi ; School of Medicine, University of Galway, University Rd, Galway, Ireland
MONZEL, Anna Sophia ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine > Developmental and Cellular Biology > Team Jens Christian SCHWAMBORN
Gomez-Giro, Gemma; Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 7, Avenue des Hauts-Fourneaux, 4362, Esch-sur-Alzette, Luxembourg
ROBERTSON, Graham ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine > Developmental and Cellular Biology > Team Jens Christian SCHWAMBORN
Jaeger, Christian; Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 7, Avenue des Hauts-Fourneaux, 4362, Esch-sur-Alzette, Luxembourg
Sharif, Jafar; Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences (IMS), Kanagawa, 230-0045, Japan
Koseki, Haruhiko ; Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences (IMS), Kanagawa, 230-0045, Japan
DIEDERICH, Nico ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine > Scientific Central Services > Disease Modelling and Screening Platform ; Centre Hospitalier de Luxembourg (CHL), 4, Rue Nicolas Ernest Barblé, L-1210, Luxembourg, Luxembourg
FLEMING, Ronan MT ; University of Luxembourg ; Metabolomics and Analytics Center, Leiden Academic Centre for Drug Research, Leiden University, 2300 RA, Leiden, The Netherlands ; School of Medicine, University of Galway, University Rd, Galway, Ireland
SCHWAMBORN, Jens Christian ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Developmental and Cellular Biology
EC | Horizon 2020 Framework Programme Fonds National de la Recherche Luxembourg
Funding text :
This work was supported by the SysMedPD project which has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 668738. Further, we acknowledge support from the National Centre of Excellence in Research on Parkinson’s Disease (NCER-PD) which is funded by the Luxembourg National Research Fund (FNR/NCER13/BM/11264123). A.Z. was supported by the Luxembourg Centre for Systems Biomedicine with an internal flagship project. We would also like to thank Dr. Nico J. Diederich and Laura Longhino from Centre Hospitalier de Luxembourg, and Thomas Rauen, Sergii Velychko, Anna-Lena Hallmann and Hans Schoeler from the Max Planck Institute in Muenster for providing iPSC lines. We thank Dr Anna Monzel for the characterization of iPSCs and the derivation of NESCs.This work was supported by the SysMedPD project which has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 668738. Further, we acknowledge support from the National Centre of Excellence in Research on Parkinson’s Disease (NCER-PD) which is funded by the Luxembourg National Research Fund (FNR/NCER13/BM/11264123). A.Z. was supported by the Luxembourg Centre for Systems Biomedicine with an internal flagship project. We would also like to thank Dr. Nico J. Diederich and Laura Longhino from Centre Hospitalier de Luxembourg, and Thomas Rauen, Sergii Velychko, Anna-Lena Hallmann and Hans Schoeler from the Max Planck Institute in Muenster for providing iPSC lines. We thank Dr Anna Monzel for the characterization of iPSCs and the derivation of NESCs.
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