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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)
Verlagsversion DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter 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
Zeitschrift Nature Communications
Quellenangaben Band: 14, Heft: 1, Seiten: , Artikelnummer: 7674 Supplement: ,
Verlag Nature Publishing Group
Verlagsort London
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) 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)
Förderungen 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