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

Bogetofte, Helle ; Jensen, Pia ; Ryding, Matias ; Schmidt, Sissel I. ; Okarmus, Justyna ; Ritter, Louise ; Worm, Christina S. ; Hohnholt, Michaela C. ; Azevedo, Carla LU and Roybon, Laurent LU , et al. (2019) In Frontiers in Cellular Neuroscience 13.
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... (More)

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.

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organization
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type
Contribution to journal
publication status
published
subject
keywords
Metabolism, Mitochondria, Oxidative stress, Parkinson’s, Proteomics, Survival
in
Frontiers in Cellular Neuroscience
volume
13
article number
297
publisher
Frontiers Media S. A.
external identifiers
  • pmid:31333417
  • scopus:85069473194
ISSN
1662-5102
DOI
10.3389/fncel.2019.00297
language
English
LU publication?
yes
id
9a547456-974f-47a7-8afb-6177eab06547
date added to LUP
2019-08-06 08:54:01
date last changed
2021-04-06 03:45:23
@article{9a547456-974f-47a7-8afb-6177eab06547,
  abstract     = {<p>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.</p>},
  author       = {Bogetofte, Helle and Jensen, Pia and Ryding, Matias and Schmidt, Sissel I. and Okarmus, Justyna and Ritter, Louise and Worm, Christina S. and Hohnholt, Michaela C. and Azevedo, Carla and Roybon, Laurent and Bak, Lasse K. and Waagepetersen, Helle and Ryan, Brent J. and Wade-Martins, Richard and Larsen, Martin R. and Meyer, Morten},
  issn         = {1662-5102},
  language     = {eng},
  month        = {07},
  publisher    = {Frontiers Media S. A.},
  series       = {Frontiers in Cellular Neuroscience},
  title        = {PARK2 mutation causes metabolic disturbances and impaired survival of human iPSC-derived neurons},
  url          = {http://dx.doi.org/10.3389/fncel.2019.00297},
  doi          = {10.3389/fncel.2019.00297},
  volume       = {13},
  year         = {2019},
}