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*

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Resumé

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.

OriginalsprogEngelsk
Artikelnummer297
TidsskriftFrontiers in Cellular Neuroscience
Vol/bind13
Antal sider14
ISSN1662-5102
DOI
StatusUdgivet - 5. jul. 2019

Fingeraftryk

Neurons
Mutation
Cell Survival
Respiration
Mitochondrial Proteins
Glycolysis
Proteome
Cell Cycle Checkpoints
Parkinson Disease
Lactic Acid
Homeostasis
Proteins
parkin protein

Citer dette

Bogetofte Thomasen, Helle ; Jensen, Pia ; Ryding, Matias Adonis Jul Gram ; Schmidt, Sissel Ida ; Okarmus, Justyna ; Ritter, Louise ; Worm, Christina Sylvest ; Hohnholt, Michaela ; Azevedo, Carla ; Roybon, Laurent ; Bak, Lasse K ; Waagepetersen, Helle S ; Ryan, Brent J. ; Wade-Martins, Richard ; Larsen, Martin Røssel ; Meyer, Morten. / PARK2 Mutation Causes Metabolic Disturbances and Impaired Survival of Human iPSC-Derived Neurons. I: Frontiers in Cellular Neuroscience. 2019 ; Bind 13.
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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.",
keywords = "Metabolism, Mitochondria, Oxidative stress, Parkinson’s, Proteomics, Survival",
author = "{Bogetofte Thomasen}, Helle and Pia Jensen and Ryding, {Matias Adonis Jul Gram} and Schmidt, {Sissel Ida} and Justyna Okarmus and Louise Ritter and Worm, {Christina Sylvest} and Michaela Hohnholt and Carla Azevedo and Laurent Roybon and Bak, {Lasse K} and Waagepetersen, {Helle S} and Ryan, {Brent J.} and Richard Wade-Martins and Larsen, {Martin R{\o}ssel} and Morten Meyer",
year = "2019",
month = "7",
day = "5",
doi = "10.3389/fncel.2019.00297",
language = "English",
volume = "13",
journal = "Frontiers in Cellular Neuroscience",
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Bogetofte Thomasen, H, Jensen, P, Ryding, MAJG, Schmidt, SI, Okarmus, J, Ritter, L, Worm, CS, Hohnholt, M, Azevedo, C, Roybon, L, Bak, LK, Waagepetersen, HS, 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, 297. https://doi.org/10.3389/fncel.2019.00297

PARK2 Mutation Causes Metabolic Disturbances and Impaired Survival of Human iPSC-Derived Neurons. / Bogetofte Thomasen, Helle; Jensen, Pia; Ryding, Matias Adonis Jul Gram; Schmidt, Sissel Ida; Okarmus, Justyna; Ritter, Louise; Worm, Christina Sylvest; Hohnholt, Michaela; Azevedo, Carla; Roybon, Laurent; Bak, Lasse K; Waagepetersen, Helle S; Ryan, Brent J.; Wade-Martins, Richard; Larsen, Martin Røssel; Meyer, Morten.

I: Frontiers in Cellular Neuroscience, Bind 13, 297, 05.07.2019.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - PARK2 Mutation Causes Metabolic Disturbances and Impaired Survival of Human iPSC-Derived Neurons

AU - Bogetofte Thomasen, Helle

AU - Jensen, Pia

AU - Ryding, Matias Adonis Jul Gram

AU - Schmidt, Sissel Ida

AU - Okarmus, Justyna

AU - Ritter, Louise

AU - Worm, Christina Sylvest

AU - Hohnholt, Michaela

AU - Azevedo, Carla

AU - Roybon, Laurent

AU - Bak, Lasse K

AU - Waagepetersen, Helle S

AU - Ryan, Brent J.

AU - Wade-Martins, Richard

AU - Larsen, Martin Røssel

AU - Meyer, Morten

PY - 2019/7/5

Y1 - 2019/7/5

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.

KW - Metabolism

KW - Mitochondria

KW - Oxidative stress

KW - Parkinson’s

KW - Proteomics

KW - Survival

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 -