PARK2 Mutation Causes Metabolic Disturbances and Impaired Survival of Human iPSC-Derived Neurons
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 mi...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-07-01
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| Series: | Frontiers in Cellular Neuroscience |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/article/10.3389/fncel.2019.00297/full |
| _version_ | 1819146975866519552 |
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| author | Helle Bogetofte 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 Morten Meyer |
| author_facet | Helle Bogetofte 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 Morten Meyer |
| author_sort | Helle Bogetofte |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-22T13:22:28Z |
| format | Article |
| id | doaj.art-76001a3b4cfe44f1a503e596795f8bcb |
| institution | Directory Open Access Journal |
| issn | 1662-5102 |
| language | English |
| last_indexed | 2024-12-22T13:22:28Z |
| publishDate | 2019-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cellular Neuroscience |
| spelling | doaj.art-76001a3b4cfe44f1a503e596795f8bcb2022-12-21T18:24:25ZengFrontiers Media S.A.Frontiers in Cellular Neuroscience1662-51022019-07-011310.3389/fncel.2019.00297448105PARK2 Mutation Causes Metabolic Disturbances and Impaired Survival of Human iPSC-Derived NeuronsHelle Bogetofte0Helle Bogetofte1Pia Jensen2Matias Ryding3Sissel I. Schmidt4Justyna Okarmus5Louise Ritter6Christina S. Worm7Michaela C. Hohnholt8Carla Azevedo9Laurent Roybon10Lasse K. Bak11Helle Waagepetersen12Brent J. Ryan13Richard Wade-Martins14Martin R. Larsen15Morten Meyer16Morten Meyer17Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, DenmarkOxford Parkinson’s Disease Centre, Medical Sciences Division, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United KingdomDepartment of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, DenmarkDepartment of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, DenmarkDepartment of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, DenmarkDepartment of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, DenmarkDepartment of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, DenmarkDepartment of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, DenmarkDepartment of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, DenmarkDepartment of Experimental Medical Science, Wallenberg Neuroscience Center, Lund University, Lund, SwedenDepartment of Experimental Medical Science, Wallenberg Neuroscience Center, Lund University, Lund, SwedenDepartment of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, DenmarkDepartment of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, DenmarkOxford Parkinson’s Disease Centre, Medical Sciences Division, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United KingdomOxford Parkinson’s Disease Centre, Medical Sciences Division, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United KingdomDepartment of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, DenmarkDepartment of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, DenmarkBrain Research – Inter-Disciplinary Guided Excellence, University of Southern Denmark, Odense, DenmarkThe 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.https://www.frontiersin.org/article/10.3389/fncel.2019.00297/fullParkinson’sproteomicsoxidative stressmetabolismsurvivalmitochondria |
| spellingShingle | Helle Bogetofte 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 Morten Meyer PARK2 Mutation Causes Metabolic Disturbances and Impaired Survival of Human iPSC-Derived Neurons Frontiers in Cellular Neuroscience Parkinson’s proteomics oxidative stress metabolism survival mitochondria |
| title | PARK2 Mutation Causes Metabolic Disturbances and Impaired Survival of Human iPSC-Derived Neurons |
| title_full | PARK2 Mutation Causes Metabolic Disturbances and Impaired Survival of Human iPSC-Derived Neurons |
| title_fullStr | PARK2 Mutation Causes Metabolic Disturbances and Impaired Survival of Human iPSC-Derived Neurons |
| title_full_unstemmed | PARK2 Mutation Causes Metabolic Disturbances and Impaired Survival of Human iPSC-Derived Neurons |
| title_short | PARK2 Mutation Causes Metabolic Disturbances and Impaired Survival of Human iPSC-Derived Neurons |
| title_sort | park2 mutation causes metabolic disturbances and impaired survival of human ipsc derived neurons |
| topic | Parkinson’s proteomics oxidative stress metabolism survival mitochondria |
| url | https://www.frontiersin.org/article/10.3389/fncel.2019.00297/full |
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