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 and Wolfgang Wurst ()
Additional contact information
Sebastian Schmidt: Helmholtz Zentrum München
Constantin Stautner: Helmholtz Zentrum München
Duc Tung Vu: Max-Planck Institute of Biochemistry
Alexander Heinz: Technische Universität Braunschweig
Martin Regensburger: University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU)
Ozge Karayel: Max-Planck Institute of Biochemistry
Dietrich Trümbach: Helmholtz Zentrum München
Anna Artati: Research Unit Molecular Endocrinology and Metabolism, Helmholtz Zentrum München
Sabine Kaltenhäuser: Technische Universität Braunschweig
Mohamed Zakaria Nassef: Technische Universität Braunschweig
Sina Hembach: Helmholtz Zentrum München
Letyfee Steinert: Helmholtz Zentrum München
Beate Winner: University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU)
Winkler Jürgen: University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU)
Martin Jastroch: 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: Technical University of Munich
Jerzy Adamski: Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health
Matthias Mann: Max-Planck Institute of Biochemistry
Karsten Hiller: Technische Universität Braunschweig
Florian Giesert: Helmholtz Zentrum München
Daniela M. Vogt Weisenhorn: Helmholtz Zentrum München
Wolfgang Wurst: Helmholtz Zentrum München

Nature Communications, 2023, vol. 14, issue 1, 1-24

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-42862-7

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