A reversible state of hypometabolism in a human cellular model of sporadic Parkinson’s disease

Sebastian Schmidt; Constantin Stautner; Duc Tung Vu; Alexander Heinz; Martin Regensburger; Ozge Karayel; Dietrich Trümbach; Anna Artati; Sabine Kaltenhäuser; Mohamed Zakaria Nassef; Sina Hembach; Letyfee Steinert; Beate Winner; Winkler Jürgen; Martin Jastroch; Malte D. Luecken; Fabian J. Theis; Gil Gregor Westmeyer; Jerzy Adamski; Matthias Mann; Karsten Hiller; Florian Giesert; Daniela M. Vogt Weisenhorn; Wolfgang Wurst

doi:10.1038/s41467-023-42862-7

Nature Communications (Nov 2023)

A reversible state of hypometabolism in a human cellular model of sporadic Parkinson’s disease

Sebastian Schmidt,
Constantin Stautner,
Duc Tung Vu,
Alexander Heinz,
Martin Regensburger,
Ozge Karayel,
Dietrich Trümbach,
Anna Artati,
Sabine Kaltenhäuser,
Mohamed Zakaria Nassef,
Sina Hembach,
Letyfee Steinert,
Beate Winner,
Winkler Jürgen,
Martin Jastroch,
Malte D. Luecken,
Fabian J. Theis,
Gil Gregor Westmeyer,
Jerzy Adamski,
Matthias Mann,
Karsten Hiller,
Florian Giesert,
Daniela M. Vogt Weisenhorn,
Wolfgang Wurst

Affiliations

Sebastian Schmidt: Institute of Developmental Genetics, Helmholtz Zentrum München
Constantin Stautner: Institute of Developmental Genetics, Helmholtz Zentrum München
Duc Tung Vu: Department for Proteomics and Signal Transduction, Max-Planck Institute of Biochemistry
Alexander Heinz: Department of Bioinformatics and Biochemistry and Braunschweig Integrated Center of Systems Biology (BRICS), Technische Universität Braunschweig
Martin Regensburger: Department of Molecular Neurology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU)
Ozge Karayel: Department for Proteomics and Signal Transduction, Max-Planck Institute of Biochemistry
Dietrich Trümbach: Institute of Developmental Genetics, Helmholtz Zentrum München
Anna Artati: Research Unit Molecular Endocrinology and Metabolism, Helmholtz Zentrum München
Sabine Kaltenhäuser: Department of Bioinformatics and Biochemistry and Braunschweig Integrated Center of Systems Biology (BRICS), Technische Universität Braunschweig
Mohamed Zakaria Nassef: Department of Bioinformatics and Biochemistry and Braunschweig Integrated Center of Systems Biology (BRICS), Technische Universität Braunschweig
Sina Hembach: Institute of Developmental Genetics, Helmholtz Zentrum München
Letyfee Steinert: Institute of Developmental Genetics, Helmholtz Zentrum München
Beate Winner: Department of Stem Cell Biology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU)
Winkler Jürgen: Department of Molecular Neurology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU)
Martin Jastroch: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University
Malte D. Luecken: Institute of Computational Biology, Helmholtz Zentrum München
Fabian J. Theis: Institute of Computational Biology, Helmholtz Zentrum München
Gil Gregor Westmeyer: Munich Institute of Biomedical Engineering, Department of Chemistry, Technical University of Munich
Jerzy Adamski: Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health
Matthias Mann: Department for Proteomics and Signal Transduction, Max-Planck Institute of Biochemistry
Karsten Hiller: Department of Bioinformatics and Biochemistry and Braunschweig Integrated Center of Systems Biology (BRICS), Technische Universität Braunschweig
Florian Giesert: Institute of Developmental Genetics, Helmholtz Zentrum München
Daniela M. Vogt Weisenhorn: Institute of Developmental Genetics, Helmholtz Zentrum München
Wolfgang Wurst: Institute of Developmental Genetics, Helmholtz Zentrum München

DOI: https://doi.org/10.1038/s41467-023-42862-7
Journal volume & issue: Vol. 14, no. 1
pp. 1 – 24

Abstract

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Abstract Sporadic Parkinson’s Disease (sPD) is a progressive neurodegenerative disorder caused by multiple genetic and environmental factors. Mitochondrial dysfunction is one contributing factor, but its role at different stages of disease progression is not fully understood. Here, we showed that neural precursor cells and dopaminergic neurons derived from induced pluripotent stem cells (hiPSCs) from sPD patients exhibited a hypometabolism. Further analysis based on transcriptomics, proteomics, and metabolomics identified the citric acid cycle, specifically the α-ketoglutarate dehydrogenase complex (OGDHC), as bottleneck in sPD metabolism. A follow-up study of the patients approximately 10 years after initial biopsy demonstrated a correlation between OGDHC activity in our cellular model and the disease progression. In addition, the alterations in cellular metabolism observed in our cellular model were restored by interfering with the enhanced SHH signal transduction in sPD. Thus, inhibiting overactive SHH signaling may have potential as neuroprotective therapy during early stages of sPD.

Published in Nature Communications

ISSN: 2041-1723 (Online)
Publisher: Nature Portfolio
Country of publisher: United Kingdom
LCC subjects: Science
Website: https://www.nature.com/ncomms/

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