A reversible state of hypometabolism in a human cellular model of sporadic Parkinson’s disease
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 ne...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-11-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-42862-7 |
| _version_ | 1797452087227842560 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Sebastian Schmidt |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-09T15:03:42Z |
| format | Article |
| id | doaj.art-221c463f9fd24a92948d727c0c8d5a38 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-09T15:03:42Z |
| publishDate | 2023-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-221c463f9fd24a92948d727c0c8d5a382023-11-26T13:46:14ZengNature PortfolioNature Communications2041-17232023-11-0114112410.1038/s41467-023-42862-7A reversible state of hypometabolism in a human cellular model of sporadic Parkinson’s diseaseSebastian Schmidt0Constantin Stautner1Duc Tung Vu2Alexander Heinz3Martin Regensburger4Ozge Karayel5Dietrich Trümbach6Anna Artati7Sabine Kaltenhäuser8Mohamed Zakaria Nassef9Sina Hembach10Letyfee Steinert11Beate Winner12Winkler Jürgen13Martin Jastroch14Malte D. Luecken15Fabian J. Theis16Gil Gregor Westmeyer17Jerzy Adamski18Matthias Mann19Karsten Hiller20Florian Giesert21Daniela M. Vogt Weisenhorn22Wolfgang Wurst23Institute of Developmental Genetics, Helmholtz Zentrum MünchenInstitute of Developmental Genetics, Helmholtz Zentrum MünchenDepartment for Proteomics and Signal Transduction, Max-Planck Institute of BiochemistryDepartment of Bioinformatics and Biochemistry and Braunschweig Integrated Center of Systems Biology (BRICS), Technische Universität BraunschweigDepartment of Molecular Neurology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU)Department for Proteomics and Signal Transduction, Max-Planck Institute of BiochemistryInstitute of Developmental Genetics, Helmholtz Zentrum MünchenResearch Unit Molecular Endocrinology and Metabolism, Helmholtz Zentrum MünchenDepartment of Bioinformatics and Biochemistry and Braunschweig Integrated Center of Systems Biology (BRICS), Technische Universität BraunschweigDepartment of Bioinformatics and Biochemistry and Braunschweig Integrated Center of Systems Biology (BRICS), Technische Universität BraunschweigInstitute of Developmental Genetics, Helmholtz Zentrum MünchenInstitute of Developmental Genetics, Helmholtz Zentrum MünchenDepartment of Stem Cell Biology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU)Department of Molecular Neurology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU)Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm UniversityInstitute of Computational Biology, Helmholtz Zentrum MünchenInstitute of Computational Biology, Helmholtz Zentrum MünchenMunich Institute of Biomedical Engineering, Department of Chemistry, Technical University of MunichInstitute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental HealthDepartment for Proteomics and Signal Transduction, Max-Planck Institute of BiochemistryDepartment of Bioinformatics and Biochemistry and Braunschweig Integrated Center of Systems Biology (BRICS), Technische Universität BraunschweigInstitute of Developmental Genetics, Helmholtz Zentrum MünchenInstitute of Developmental Genetics, Helmholtz Zentrum MünchenInstitute of Developmental Genetics, Helmholtz Zentrum MünchenAbstract 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.https://doi.org/10.1038/s41467-023-42862-7 |
| spellingShingle | 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 A reversible state of hypometabolism in a human cellular model of sporadic Parkinson’s disease Nature Communications |
| title | A reversible state of hypometabolism in a human cellular model of sporadic Parkinson’s disease |
| title_full | A reversible state of hypometabolism in a human cellular model of sporadic Parkinson’s disease |
| title_fullStr | A reversible state of hypometabolism in a human cellular model of sporadic Parkinson’s disease |
| title_full_unstemmed | A reversible state of hypometabolism in a human cellular model of sporadic Parkinson’s disease |
| title_short | A reversible state of hypometabolism in a human cellular model of sporadic Parkinson’s disease |
| title_sort | reversible state of hypometabolism in a human cellular model of sporadic parkinson s disease |
| url | https://doi.org/10.1038/s41467-023-42862-7 |
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