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

doi:10.1016/j.isci.2023.107044

Calcium dysregulation combined with mitochondrial failure and electrophysiological maturity converge in Parkinson's iPSC-dopamine neurons

iScience. 2023 Jun 7;26(7):107044. doi: 10.1016/j.isci.2023.107044. eCollection 2023 Jul 21.

Authors

Dayne A Beccano-Kelly^{1

2}, Marta Cherubini^{1

2}, Yassine Mousba^{1

2}, Kaitlyn M L Cramb^{1

2

3}, Stefania Giussani^{1

2}, Maria Claudia Caiazza^{1

2

3}, Pavandeep Rai^{1

2}, Siv Vingill^{1

2}, Nora Bengoa-Vergniory^{1

2

3}, Bryan Ng^{2

3}, Gabriele Corda², Abhirup Banerjee^{4

5}, Jane Vowles^{1

6}, Sally Cowley^{1

6}, Richard Wade-Martins^{1

2

3}

Affiliations

¹ Oxford Parkinson's Disease Centre, University of Oxford, Oxford, United Kingdom.
² Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX3 7BN, UK.
³ Kavli Institute for Nanoscience Discovery, University of Oxford, Dorothy Crowfoot Hodgkin Building, South Parks Road, Oxford OX1 3QU, UK.
⁴ Radcliffe Department of Medicine, Division of Cardiovascular Medicine, University of Oxford, Oxford OX3 9DU, UK.
⁵ Department of Engineering Science, Institute of Biomedical Engineering, University of Oxford, Oxford OX3 7DQ, UK.
⁶ The James Martin Stem Cell Facility, Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK.

Abstract

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.

Keywords: Cellular neuroscience; Pathophysiology; Stem cells research.

Abstract

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