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Schmidt, S. ; Stautner, C. ; Vu, D.T.* ; Heinz, A.* ; Regensburger, M.* ; Karayel, O.* ; Trümbach, D. ; Artati, A. ; Kaltenhäuser, S.* ; Nassef, M.Z.* ; Hembach, S. ; Steinert, L. ; Winner, B.* ; Jürgen, W.* ; Jastroch, M.* ; Luecken, M. ; Theis, F.J. ; Westmeyer, G.G. ; Adamski, J. ; Mann, M.* ; Hiller, K.* ; Giesert, F. ; Vogt Weisenhorn, D.M. ; Wurst, W.

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

Nat. Commun. 14:7674 (2023)

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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.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Complex-i Deficiency; Ketoglutarate Dehydrogenase; Computational Platform; Comprehensive Analysis; Sonic Hedgehog; Acid Cycle; Brain; Mitochondria; Glucose; Enzyme

ISSN (print) / ISBN 2041-1723

e-ISSN 2041-1723

Journal Nature Communications

Quellenangaben Volume: 14, Issue: 1, Article Number: 7674

Publisher Nature Publishing Group

Publishing Place London

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Developmental Genetics (IDG)
Molekulare Endokrinologie und Metabolismus (MEM)
Institute of Computational Biology (ICB)
Insitute of Synthetic Biomedicine (ISBM)
Institute of Experimental Genetics (IEG)
Institute of Metabolism and Cell Death (MCD)

Grants Helmholtz Association through the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)
Helmholtz Association through the Niedersaechsisches Vorab
German Federal Ministry of Education and Research (BMBF)
German Federal Ministry of Education and Research (BMBF) through ACS_iIMMUNE
ForInter consortium
Bavarian Ministry of Science and the Arts in the framework of the ForIPS consortium