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

Author

Listed:
  • Sebastian Schmidt

    (Helmholtz Zentrum München
    Technical University of Munich)

  • Constantin Stautner

    (Helmholtz Zentrum München)

  • Duc Tung Vu

    (Max-Planck Institute of Biochemistry)

  • Alexander Heinz

    (Technische Universität Braunschweig)

  • Martin Regensburger

    (University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU))

  • Ozge Karayel

    (Max-Planck Institute of Biochemistry)

  • Dietrich Trümbach

    (Helmholtz Zentrum München
    Institute of Metabolism and Cell Death, Helmholtz Zentrum München)

  • Anna Artati

    (Research Unit Molecular Endocrinology and Metabolism, Helmholtz Zentrum München)

  • Sabine Kaltenhäuser

    (Technische Universität Braunschweig)

  • Mohamed Zakaria Nassef

    (Technische Universität Braunschweig)

  • Sina Hembach

    (Helmholtz Zentrum München)

  • Letyfee Steinert

    (Helmholtz Zentrum München)

  • Beate Winner

    (University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU))

  • Winkler Jürgen

    (University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU))

  • Martin Jastroch

    (Stockholm University)

  • Malte D. Luecken

    (Institute of Computational Biology, Helmholtz Zentrum München)

  • Fabian J. Theis

    (Institute of Computational Biology, Helmholtz Zentrum München
    Technische Universität München)

  • Gil Gregor Westmeyer

    (Technical University of Munich
    Institute for Synthetic Biomedicine, Helmholtz Zentrum München)

  • Jerzy Adamski

    (Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health
    National University of Singapore
    University of Ljubljana)

  • Matthias Mann

    (Max-Planck Institute of Biochemistry
    University of Copenhagen)

  • Karsten Hiller

    (Technische Universität Braunschweig)

  • Florian Giesert

    (Helmholtz Zentrum München)

  • Daniela M. Vogt Weisenhorn

    (Helmholtz Zentrum München)

  • Wolfgang Wurst

    (Helmholtz Zentrum München
    Munich School of Life Sciences Weihenstephan, Technical University of Munich
    Munich Cluster of Systems Neurology (SyNergy)
    German Center for Neurodegenerative Diseases (DZNE) site Munich)

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.

Suggested Citation

  • Sebastian Schmidt & Constantin Stautner & Duc Tung Vu & Alexander Heinz & Martin Regensburger & Ozge Karayel & Dietrich Trümbach & Anna Artati & Sabine Kaltenhäuser & Mohamed Zakaria Nassef & Sina Hem, 2023. "A reversible state of hypometabolism in a human cellular model of sporadic Parkinson’s disease," Nature Communications, Nature, vol. 14(1), pages 1-24, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42862-7
    DOI: 10.1038/s41467-023-42862-7
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    References listed on IDEAS

    as
    1. Sebastian Schmidt & Malte D. Luecken & Dietrich Trümbach & Sina Hembach & Kristina M. Niedermeier & Nicole Wenck & Klaus Pflügler & Constantin Stautner & Anika Böttcher & Heiko Lickert & Ciro Ramirez-, 2022. "Primary cilia and SHH signaling impairments in human and mouse models of Parkinson’s disease," Nature Communications, Nature, vol. 13(1), pages 1-25, December.
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