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

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

Journal: Nature communications 2023;14(1):7674

PMID: 37996418

Free Full Text on Nature Publishing Group View on PubMed

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.

Address: Institute of Developmental Genetics, Helmholtz Zentrum München, Neuherberg, Germany. [email protected].; Munich Institute of Biomedical Engineering, Department of Chemistry, Technical University of Munich, Munich, Germany. [email protected].; Institute of Developmental Genetics, Helmholtz Zentrum München, Neuherberg, Germany.; Department for Proteomics and Signal Transduction, Max-Planck Institute of Biochemistry, Martinsried, Germany.; Department of Bioinformatics and Biochemistry and Braunschweig Integrated Center of Systems Biology (BRICS), Technische Universität Braunschweig, Braunschweig, Germany.; Department of Molecular Neurology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.; Institute of Metabolism and Cell Death, Helmholtz Zentrum München, Neuherberg, Germany.; Research Unit Molecular Endocrinology and Metabolism, Helmholtz Zentrum München, Neuherberg, Germany.; Department of Stem Cell Biology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.; Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.; Institute of Computational Biology, Helmholtz Zentrum München, Neuherberg, Germany.; Department of Mathematics, Technische Universität München, Garching bei München, Germany.; Munich Institute of Biomedical Engineering, Department of Chemistry, Technical University of Munich, Munich, Germany.; Institute for Synthetic Biomedicine, Helmholtz Zentrum München, Neuherberg, Germany.; Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.; Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.; NNF Center for Protein Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.; Institute of Developmental Genetics, Helmholtz Zentrum München, Neuherberg, Germany. [email protected].; Chair of Developmental Genetics, Munich School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany. [email protected].; Munich Cluster of Systems Neurology (SyNergy), Munich, Germany. [email protected].; German Center for Neurodegenerative Diseases (DZNE) site Munich, Munich, Germany. [email protected].

DOI: 10.1038/s41467-023-42862-7

Link outs

Free resources

Full Text Sources:

Medical:

https://medlineplus.gov/parkinsonsdisease.html

MeSH Terms: Humans, Parkinson Disease, Neural Stem Cells, Follow-Up Studies, Dopaminergic Neurons, Disease Progression