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

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

doi:10.3389/fncel.2019.00297

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

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

21 Citationer (Scopus)

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.

Originalsprog	Engelsk
Tidsskrift	Frontiers in Cellular Neuroscience
Vol/bind	13
Sider (fra-til)	297
ISSN	1662-5102
DOI	https://doi.org/10.3389/fncel.2019.00297
Status	Udgivet - 16 jul. 2019

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10.3389/fncel.2019.00297

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Bogetofte, H., Jensen, P., Ryding, M., Schmidt, S. I., Okarmus, J., Ritter, L., Worm, C. S., Hohnholt, M. C., Azevedo, C., Roybon, L., Bak, L. K., Waagepetersen, H., 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

Bogetofte, H, Jensen, P, Ryding, M, Schmidt, SI, Okarmus, J, Ritter, L, Worm, CS, Hohnholt, MC, Azevedo, C, Roybon, L, Bak, LK , Waagepetersen, H, Ryan, BJ, Wade-Martins, R, Larsen, MR & Meyer, M 2019, 'PARK2 Mutation Causes Metabolic Disturbances and Impaired Survival of Human iPSC-Derived Neurons', Frontiers in Cellular Neuroscience, bind 13, s. 297. https://doi.org/10.3389/fncel.2019.00297

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title = "PARK2 Mutation Causes Metabolic Disturbances and Impaired Survival of Human iPSC-Derived Neurons",

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.",

author = "Helle Bogetofte and Pia Jensen and Matias Ryding and Schmidt, {Sissel I} and Justyna Okarmus and Louise Ritter and Worm, {Christina S} and Hohnholt, {Michaela C} and Carla Azevedo and Laurent Roybon and Bak, {Lasse K} and Helle Waagepetersen and Ryan, {Brent J} and Richard Wade-Martins and Larsen, {Martin R} and Morten Meyer",

year = "2019",

month = jul,

day = "16",

doi = "10.3389/fncel.2019.00297",

language = "English",

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journal = "Frontiers in Cellular Neuroscience",

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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 - 2019/7/16

Y1 - 2019/7/16

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

SN - 1662-5102

VL - 13

SP - 297

JO - Frontiers in Cellular Neuroscience

JF - Frontiers in Cellular Neuroscience

ER -

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

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