Calcium dysregulation combined with mitochondrial failure and electrophysiological maturity converge in Parkinson’s iPSC-dopamine neurons
Summary: Parkinson’s disease (PD) is characterized by a progressive deterioration of motor and cognitive functions. Although death of dopamine neurons is the hallmark pathology of PD, this is a late-stage disease process preceded by neuronal dysfunction. Here we describe early physiological perturba...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-07-01
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| Series: | iScience |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004223011215 |
| _version_ | 1827895602312118272 |
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| author | Dayne A. Beccano-Kelly Marta Cherubini Yassine Mousba Kaitlyn M.L. Cramb Stefania Giussani Maria Claudia Caiazza Pavandeep Rai Siv Vingill Nora Bengoa-Vergniory Bryan Ng Gabriele Corda Abhirup Banerjee Jane Vowles Sally Cowley Richard Wade-Martins |
| author_facet | Dayne A. Beccano-Kelly Marta Cherubini Yassine Mousba Kaitlyn M.L. Cramb Stefania Giussani Maria Claudia Caiazza Pavandeep Rai Siv Vingill Nora Bengoa-Vergniory Bryan Ng Gabriele Corda Abhirup Banerjee Jane Vowles Sally Cowley Richard Wade-Martins |
| author_sort | Dayne A. Beccano-Kelly |
| collection | DOAJ |
| description | Summary: Parkinson’s disease (PD) is characterized by a progressive deterioration of motor and cognitive functions. Although death of dopamine neurons is the hallmark pathology of PD, this is a late-stage disease process preceded by neuronal dysfunction. Here we describe early physiological perturbations in patient-derived induced pluripotent stem cell (iPSC)-dopamine neurons carrying the GBA-N370S mutation, a strong genetic risk factor for PD. GBA-N370S iPSC-dopamine neurons show an early and persistent calcium dysregulation notably at the mitochondria, followed by reduced mitochondrial membrane potential and oxygen consumption rate, indicating mitochondrial failure. With increased neuronal maturity, we observed decreased synaptic function in PD iPSC-dopamine neurons, consistent with the requirement for ATP and calcium to support the increase in electrophysiological activity over time. Our work demonstrates that calcium dyshomeostasis and mitochondrial failure impair the higher electrophysiological activity of mature neurons and may underlie the vulnerability of dopamine neurons in PD. |
| first_indexed | 2024-03-12T22:23:15Z |
| format | Article |
| id | doaj.art-f5a07e41be014a9c8bc7c3737d815059 |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-03-12T22:23:15Z |
| publishDate | 2023-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-f5a07e41be014a9c8bc7c3737d8150592023-07-23T04:55:18ZengElsevieriScience2589-00422023-07-01267107044Calcium dysregulation combined with mitochondrial failure and electrophysiological maturity converge in Parkinson’s iPSC-dopamine neuronsDayne A. Beccano-Kelly0Marta Cherubini1Yassine Mousba2Kaitlyn M.L. Cramb3Stefania Giussani4Maria Claudia Caiazza5Pavandeep Rai6Siv Vingill7Nora Bengoa-Vergniory8Bryan Ng9Gabriele Corda10Abhirup Banerjee11Jane Vowles12Sally Cowley13Richard Wade-Martins14Oxford Parkinson’s Disease Centre, University of Oxford, Oxford, United Kingdom; Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX3 7BN, UKOxford Parkinson’s Disease Centre, University of Oxford, Oxford, United Kingdom; Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX3 7BN, UKOxford Parkinson’s Disease Centre, University of Oxford, Oxford, United Kingdom; Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX3 7BN, UKOxford Parkinson’s Disease Centre, University of Oxford, Oxford, United Kingdom; Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX3 7BN, UK; Kavli Institute for Nanoscience Discovery, University of Oxford, Dorothy Crowfoot Hodgkin Building, South Parks Road, Oxford OX1 3QU, UKOxford Parkinson’s Disease Centre, University of Oxford, Oxford, United Kingdom; Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX3 7BN, UKOxford Parkinson’s Disease Centre, University of Oxford, Oxford, United Kingdom; Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX3 7BN, UK; Kavli Institute for Nanoscience Discovery, University of Oxford, Dorothy Crowfoot Hodgkin Building, South Parks Road, Oxford OX1 3QU, UKOxford Parkinson’s Disease Centre, University of Oxford, Oxford, United Kingdom; Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX3 7BN, UKOxford Parkinson’s Disease Centre, University of Oxford, Oxford, United Kingdom; Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX3 7BN, UKOxford Parkinson’s Disease Centre, University of Oxford, Oxford, United Kingdom; Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX3 7BN, UK; Kavli Institute for Nanoscience Discovery, University of Oxford, Dorothy Crowfoot Hodgkin Building, South Parks Road, Oxford OX1 3QU, UKDepartment of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX3 7BN, UK; Kavli Institute for Nanoscience Discovery, University of Oxford, Dorothy Crowfoot Hodgkin Building, South Parks Road, Oxford OX1 3QU, UKDepartment of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX3 7BN, UKRadcliffe Department of Medicine, Division of Cardiovascular Medicine, University of Oxford, Oxford OX3 9DU, UK; Department of Engineering Science, Institute of Biomedical Engineering, University of Oxford, Oxford OX3 7DQ, UKOxford Parkinson’s Disease Centre, University of Oxford, Oxford, United Kingdom; The James Martin Stem Cell Facility, Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UKOxford Parkinson’s Disease Centre, University of Oxford, Oxford, United Kingdom; The James Martin Stem Cell Facility, Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UKOxford Parkinson’s Disease Centre, University of Oxford, Oxford, United Kingdom; Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX3 7BN, UK; Kavli Institute for Nanoscience Discovery, University of Oxford, Dorothy Crowfoot Hodgkin Building, South Parks Road, Oxford OX1 3QU, UK; Corresponding authorSummary: Parkinson’s disease (PD) is characterized by a progressive deterioration of motor and cognitive functions. Although death of dopamine neurons is the hallmark pathology of PD, this is a late-stage disease process preceded by neuronal dysfunction. Here we describe early physiological perturbations in patient-derived induced pluripotent stem cell (iPSC)-dopamine neurons carrying the GBA-N370S mutation, a strong genetic risk factor for PD. GBA-N370S iPSC-dopamine neurons show an early and persistent calcium dysregulation notably at the mitochondria, followed by reduced mitochondrial membrane potential and oxygen consumption rate, indicating mitochondrial failure. With increased neuronal maturity, we observed decreased synaptic function in PD iPSC-dopamine neurons, consistent with the requirement for ATP and calcium to support the increase in electrophysiological activity over time. Our work demonstrates that calcium dyshomeostasis and mitochondrial failure impair the higher electrophysiological activity of mature neurons and may underlie the vulnerability of dopamine neurons in PD.http://www.sciencedirect.com/science/article/pii/S2589004223011215PathophysiologyCellular neuroscienceStem cells research |
| spellingShingle | Dayne A. Beccano-Kelly Marta Cherubini Yassine Mousba Kaitlyn M.L. Cramb Stefania Giussani Maria Claudia Caiazza Pavandeep Rai Siv Vingill Nora Bengoa-Vergniory Bryan Ng Gabriele Corda Abhirup Banerjee Jane Vowles Sally Cowley Richard Wade-Martins Calcium dysregulation combined with mitochondrial failure and electrophysiological maturity converge in Parkinson’s iPSC-dopamine neurons iScience Pathophysiology Cellular neuroscience Stem cells research |
| title | Calcium dysregulation combined with mitochondrial failure and electrophysiological maturity converge in Parkinson’s iPSC-dopamine neurons |
| title_full | Calcium dysregulation combined with mitochondrial failure and electrophysiological maturity converge in Parkinson’s iPSC-dopamine neurons |
| title_fullStr | Calcium dysregulation combined with mitochondrial failure and electrophysiological maturity converge in Parkinson’s iPSC-dopamine neurons |
| title_full_unstemmed | Calcium dysregulation combined with mitochondrial failure and electrophysiological maturity converge in Parkinson’s iPSC-dopamine neurons |
| title_short | Calcium dysregulation combined with mitochondrial failure and electrophysiological maturity converge in Parkinson’s iPSC-dopamine neurons |
| title_sort | calcium dysregulation combined with mitochondrial failure and electrophysiological maturity converge in parkinson s ipsc dopamine neurons |
| topic | Pathophysiology Cellular neuroscience Stem cells research |
| url | http://www.sciencedirect.com/science/article/pii/S2589004223011215 |
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