PARK2 Mutation Causes Metabolic Disturbances and Impaired Survival of Human iPSC-Derived Neurons

Helle Bogetofte Thomasen, Pia Jensen, Matias Adonis Jul Gram Ryding, Sissel Ida Schmidt, Justyna Okarmus, Louise Ritter, Christina Sylvest Worm, Michaela Hohnholt, Carla Azevedo, Laurent Roybon, Lasse K Bak, Helle S Waagepetersen, Brent J. Ryan, Richard Wade-Martins, Martin Røssel Larsen, Morten Meyer*

*Corresponding author for this work

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Abstract

The protein parkin, encoded by the PARK2 gene, is vital for mitochondrial homeostasis, and although it has been implicated in Parkinson’s disease (PD), the disease mechanisms remain unclear. We have applied mass spectrometry-based proteomics to investigate the effects of parkin dysfunction on the mitochondrial proteome in human isogenic induced pluripotent stem cell-derived neurons with and without PARK2 knockout (KO). The proteomic analysis quantified nearly 60% of all mitochondrial proteins, 119 of which were dysregulated in neurons with PARK2 KO. The protein changes indicated disturbances in oxidative stress defense, mitochondrial respiration and morphology, cell cycle control, and cell viability. Structural and functional analyses revealed an increase in mitochondrial area and the presence of elongated mitochondria as well as impaired glycolysis and lactate-supported respiration, leading to an impaired cell survival in PARK2 KO neurons. This adds valuable insight into the effect of parkin dysfunction in human neurons and provides knowledge of disease-related pathways that can potentially be targeted for therapeutic intervention.

Original languageEnglish
Article number297
JournalFrontiers in Cellular Neuroscience
Volume13
Number of pages14
ISSN1662-5102
DOIs
Publication statusPublished - 5. Jul 2019

Keywords

  • Metabolism
  • Mitochondria
  • Oxidative stress
  • Parkinson’s
  • Proteomics
  • Survival

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    Bogetofte Thomasen, H., Jensen, P., Ryding, M. A. J. G., Schmidt, S. I., Okarmus, J., Ritter, L., Worm, C. S., Hohnholt, M., Azevedo, C., Roybon, L., Bak, L. K., Waagepetersen, H. S., Ryan, B. J., Wade-Martins, R., Larsen, M. R., & Meyer, M. (2019). PARK2 Mutation Causes Metabolic Disturbances and Impaired Survival of Human iPSC-Derived Neurons. Frontiers in Cellular Neuroscience, 13, [297]. https://doi.org/10.3389/fncel.2019.00297