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Plate IV.167 · Publications

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

Article in Nature Communications, 23 November 2023.

Open accessBrain, Neurons, Reprogramming

  1. Sebastian Schmidt
  2. Constantin Stautner
  3. Duc Tung Vu
  4. Alexander Heinz
  5. Martin Regensburger
  6. Ozge Karayel
  7. Dietrich Trümbach
  8. Anna Artati
  9. Sabine Kaltenhäuser
  10. Mohamed Zakaria Nassef
  11. Sina Hembach
  12. Letyfee Steinert
  13. Beate Winner
  14. Winkler Jürgen
  15. Martin Jastroch
  16. Malte D. Luecken
  17. Fabian J. Theis
  18. Gil Gregor Westmeyer
  19. Jerzy Adamski
  20. Matthias Mann
  21. Karsten Hiller
  22. Florian Giesert
  23. Daniela M. Vogt Weisenhorn
  24. Wolfgang Wurst

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.

Cite

@article{schmidt2023reversible,
  title = {{A reversible state of hypometabolism in a human cellular model of sporadic Parkinson’s disease}},
  author = {Schmidt, Sebastian and Stautner, Constantin and Vu, Duc Tung and Heinz, Alexander and Regensburger, Martin and Karayel, Ozge and Trümbach, Dietrich and Artati, Anna and Kaltenhäuser, Sabine and Nassef, Mohamed Zakaria and Hembach, Sina and Steinert, Letyfee and Winner, Beate and Jürgen, Winkler and Jastroch, Martin and Luecken, Malte D. and Theis, Fabian J. and Westmeyer, Gil Gregor and Adamski, Jerzy and Mann, Matthias and Hiller, Karsten and Giesert, Florian and Vogt Weisenhorn, Daniela M. and Wurst, Wolfgang},
  journal = {Nature Communications},
  publisher = {Springer Science and Business Media LLC},
  year = {2023},
  month = nov,
  doi = {10.1038/s41467-023-42862-7},
  url = {https://doi.org/10.1038/s41467-023-42862-7},
  pmid = {37996418},
  pmcid = {PMC10667251}
}
.bib file