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

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

Nat Commun. 2023 Nov 23;14(1):7674. doi: 10.1038/s41467-023-42862-7.

Authors

Sebastian Schmidt^{1

2}, Constantin Stautner³, Duc Tung Vu⁴, Alexander Heinz⁵, Martin Regensburger⁶, Ozge Karayel⁴, Dietrich Trümbach^{3

7}, Anna Artati⁸, Sabine Kaltenhäuser⁵, Mohamed Zakaria Nassef⁵, Sina Hembach³, Letyfee Steinert³, Beate Winner⁹, Winkler Jürgen⁶, Martin Jastroch¹⁰, Malte D Luecken¹¹, Fabian J Theis^{11

12}, Gil Gregor Westmeyer^{13

14}, Jerzy Adamski^{15

16

17}, Matthias Mann^{4

18}, Karsten Hiller⁵, Florian Giesert³, Daniela M Vogt Weisenhorn³, Wolfgang Wurst^{19

20

21

22}

Affiliations

¹ Institute of Developmental Genetics, Helmholtz Zentrum München, Neuherberg, Germany. [email protected].
² Munich Institute of Biomedical Engineering, Department of Chemistry, Technical University of Munich, Munich, Germany. [email protected].
³ Institute of Developmental Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
⁴ Department for Proteomics and Signal Transduction, Max-Planck Institute of Biochemistry, Martinsried, Germany.
⁵ Department of Bioinformatics and Biochemistry and Braunschweig Integrated Center of Systems Biology (BRICS), Technische Universität Braunschweig, Braunschweig, Germany.
⁶ Department of Molecular Neurology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.
⁷ Institute of Metabolism and Cell Death, Helmholtz Zentrum München, Neuherberg, Germany.
⁸ Research Unit Molecular Endocrinology and Metabolism, Helmholtz Zentrum München, Neuherberg, Germany.
⁹ Department of Stem Cell Biology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.
¹⁰ Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
¹¹ Institute of Computational Biology, Helmholtz Zentrum München, Neuherberg, Germany.
¹² Department of Mathematics, Technische Universität München, Garching bei München, Germany.
¹³ Munich Institute of Biomedical Engineering, Department of Chemistry, Technical University of Munich, Munich, Germany.
¹⁴ Institute for Synthetic Biomedicine, Helmholtz Zentrum München, Neuherberg, Germany.
¹⁵ Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
¹⁶ Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
¹⁷ Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
¹⁸ NNF Center for Protein Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
¹⁹ Institute of Developmental Genetics, Helmholtz Zentrum München, Neuherberg, Germany. [email protected].
²⁰ Chair of Developmental Genetics, Munich School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany. [email protected].
²¹ Munich Cluster of Systems Neurology (SyNergy), Munich, Germany. [email protected].
²² German Center for Neurodegenerative Diseases (DZNE) site Munich, Munich, Germany. [email protected].

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.

MeSH terms

Disease Progression
Dopaminergic Neurons / metabolism
Follow-Up Studies
Humans
Neural Stem Cells* / metabolism
Parkinson Disease* / metabolism