PARK2 Mutation Causes Metabolic Disturbances and Impaired Survival of Human iPSC-Derived Neurons
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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; Roybon, Laurent; Bak, Lasse K; Waagepetersen, Helle; Ryan, Brent J; Wade-Martins, Richard; Larsen, Martin R; Meyer, Morten.
In: Frontiers in Cellular Neuroscience, Vol. 13, 297, 2019.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - PARK2 Mutation Causes Metabolic Disturbances and Impaired Survival of Human iPSC-Derived Neurons
AU - Bogetofte, Helle
AU - Jensen, Pia
AU - Ryding, Matias
AU - Schmidt, Sissel I
AU - Okarmus, Justyna
AU - Ritter, Louise
AU - Worm, Christina S
AU - Hohnholt, Michaela C
AU - Azevedo, Carla
AU - Roybon, Laurent
AU - Bak, Lasse K
AU - Waagepetersen, Helle
AU - Ryan, Brent J
AU - Wade-Martins, Richard
AU - Larsen, Martin R
AU - Meyer, Morten
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
U2 - 10.3389/fncel.2019.00297
DO - 10.3389/fncel.2019.00297
M3 - Journal article
C2 - 31333417
VL - 13
JO - Frontiers in Cellular Neuroscience
JF - Frontiers in Cellular Neuroscience
SN - 1662-5102
M1 - 297
ER -
ID: 225950001