Calcium dysregulation combined with mitochondrial failure and electrophysiological maturity converge in Parkinson’s iPSC-dopamine neurons
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
Affiliations
Dayne A. Beccano-Kelly
Oxford 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
Marta Cherubini
Oxford 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
Yassine Mousba
Oxford 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
Kaitlyn M.L. Cramb
Oxford 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
Stefania Giussani
Oxford 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
Maria Claudia Caiazza
Oxford 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
Pavandeep Rai
Oxford 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
Siv Vingill
Oxford 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
Nora Bengoa-Vergniory
Oxford 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
Bryan Ng
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
Gabriele Corda
Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX3 7BN, UK
Abhirup Banerjee
Radcliffe 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, UK
Jane Vowles
Oxford 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, UK
Sally Cowley
Oxford 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, UK
Richard Wade-Martins
Oxford 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 author
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.
