PARK2 mutation causes metabolic disturbances and impaired survival of human iPSC-derived neurons

Research output: Contribution to journalArticle

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.

Details

Authors
  • Helle Bogetofte
  • Pia Jensen
  • Matias Ryding
  • Sissel I. Schmidt
  • Justyna Okarmus
  • Louise Ritter
  • Christina S. Worm
  • Michaela C. Hohnholt
  • Carla Azevedo
  • Laurent Roybon
  • Lasse K. Bak
  • Helle Waagepetersen
  • Brent J. Ryan
  • Richard Wade-Martins
  • Martin R. Larsen
  • Morten Meyer
Organisations
External organisations
  • University of Southern Denmark
  • University of Oxford
  • University of Copenhagen
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Neurosciences

Keywords

  • Metabolism, Mitochondria, Oxidative stress, Parkinson’s, Proteomics, Survival
Original languageEnglish
Article number297
JournalFrontiers in Cellular Neuroscience
Volume13
Publication statusPublished - 2019 Jul 5
Publication categoryResearch
Peer-reviewedYes