Calcium dysregulation combined with mitochondrial failure and electrophysiological maturity converge in Parkinson’s iPSC-dopamine neurons
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...
| Autores principales: | , , , , , , , , , , , , , , |
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| Formato: | Journal article |
| Lenguaje: | English |
| Publicado: |
Cell Press
2023
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| _version_ | 1826311567849816064 |
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| author | Beccano-Kelly, DA Cherubini, M Mousba, Y Cramb, KML Giussani, S Caiazza, MC Rai, P Vingill, S Bengoa-Vergniory, N Ng, B Corda, G Banerjee, A Vowles, J Cowley, S Wade-Martins, R |
| author_facet | Beccano-Kelly, DA Cherubini, M Mousba, Y Cramb, KML Giussani, S Caiazza, MC Rai, P Vingill, S Bengoa-Vergniory, N Ng, B Corda, G Banerjee, A Vowles, J Cowley, S Wade-Martins, R |
| author_sort | Beccano-Kelly, DA |
| collection | OXFORD |
| description | 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 <i>GBA-N370S</i> mutation, a strong genetic risk factor for PD. <i>GBA-N370S</i> 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 | 2024-03-07T08:11:41Z |
| format | Journal article |
| id | oxford-uuid:d2f9afc1-d797-450c-bc95-4cda9c97eea1 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T08:11:41Z |
| publishDate | 2023 |
| publisher | Cell Press |
| record_format | dspace |
| spelling | oxford-uuid:d2f9afc1-d797-450c-bc95-4cda9c97eea12023-11-30T16:58:53ZCalcium dysregulation combined with mitochondrial failure and electrophysiological maturity converge in Parkinson’s iPSC-dopamine neuronsJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:d2f9afc1-d797-450c-bc95-4cda9c97eea1EnglishSymplectic ElementsCell Press2023Beccano-Kelly, DACherubini, MMousba, YCramb, KMLGiussani, SCaiazza, MCRai, PVingill, SBengoa-Vergniory, NNg, BCorda, GBanerjee, AVowles, JCowley, SWade-Martins, RParkinson’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 <i>GBA-N370S</i> mutation, a strong genetic risk factor for PD. <i>GBA-N370S</i> 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. |
| spellingShingle | Beccano-Kelly, DA Cherubini, M Mousba, Y Cramb, KML Giussani, S Caiazza, MC Rai, P Vingill, S Bengoa-Vergniory, N Ng, B Corda, G Banerjee, A Vowles, J Cowley, S Wade-Martins, R Calcium dysregulation combined with mitochondrial failure and electrophysiological maturity converge in Parkinson’s iPSC-dopamine neurons |
| 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 |
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