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Restriction of mitochondrial calcium overload by mcu inactivation renders a neuroprotective effect in zebrafish models of Parkinson's disease
The loss of dopaminergic neurons (DA) is a pathological hallmark of sporadic and familial forms of Parkinson's disease (PD). We have previously shown that inhibiting mitochondrial calcium uniporter (mcu) using morpholinos can rescue DA neurons in the PTEN-induced putative kinase 1 (pink1)(−/−)...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Company of Biologists Ltd
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826286/ https://www.ncbi.nlm.nih.gov/pubmed/31548178 http://dx.doi.org/10.1242/bio.044347 |
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author | Soman, Smijin K. Bazała, Michal Keatinge, Marcus Bandmann, Oliver Kuznicki, Jacek |
author_facet | Soman, Smijin K. Bazała, Michal Keatinge, Marcus Bandmann, Oliver Kuznicki, Jacek |
author_sort | Soman, Smijin K. |
collection | PubMed |
description | The loss of dopaminergic neurons (DA) is a pathological hallmark of sporadic and familial forms of Parkinson's disease (PD). We have previously shown that inhibiting mitochondrial calcium uniporter (mcu) using morpholinos can rescue DA neurons in the PTEN-induced putative kinase 1 (pink1)(−/−) zebrafish model of PD. In this article, we show results from our studies in mcu knockout zebrafish, which was generated using the CRISPR/Cas9 system. Functional assays confirmed impaired mitochondrial calcium influx in mcu(−/−) zebrafish. We also used in vivo calcium imaging and fluorescent assays in purified mitochondria to investigate mitochondrial calcium dynamics in a pink1(−/−) zebrafish model of PD. Mitochondrial morphology was evaluated in DA neurons and muscle fibers using immunolabeling and transgenic lines, respectively. We observed diminished mitochondrial area in DA neurons of pink1(−/−) zebrafish, while deletion of mcu restored mitochondrial area. In contrast, the mitochondrial volume in muscle fibers was not restored after inactivation of mcu in pink1(−/−) zebrafish. Mitochondrial calcium overload coupled with depolarization of mitochondrial membrane potential leads to mitochondrial dysfunction in the pink1(−/−) zebrafish model of PD. We used in situ hybridization and immunohistochemical labeling of DA neurons to evaluate the effect of mcu deletion on DA neuronal clusters in the ventral telencephalon of zebrafish brain. We show that DA neurons are rescued after deletion of mcu in pink1(−/−) and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) zebrafish model of PD. Thus, inactivation of mcu is protective in both genetic and chemical models of PD. Our data reveal that regulating mcu function could be an effective therapeutic target in PD pathology. |
format | Online Article Text |
id | pubmed-6826286 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | The Company of Biologists Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-68262862019-11-04 Restriction of mitochondrial calcium overload by mcu inactivation renders a neuroprotective effect in zebrafish models of Parkinson's disease Soman, Smijin K. Bazała, Michal Keatinge, Marcus Bandmann, Oliver Kuznicki, Jacek Biol Open Research Article The loss of dopaminergic neurons (DA) is a pathological hallmark of sporadic and familial forms of Parkinson's disease (PD). We have previously shown that inhibiting mitochondrial calcium uniporter (mcu) using morpholinos can rescue DA neurons in the PTEN-induced putative kinase 1 (pink1)(−/−) zebrafish model of PD. In this article, we show results from our studies in mcu knockout zebrafish, which was generated using the CRISPR/Cas9 system. Functional assays confirmed impaired mitochondrial calcium influx in mcu(−/−) zebrafish. We also used in vivo calcium imaging and fluorescent assays in purified mitochondria to investigate mitochondrial calcium dynamics in a pink1(−/−) zebrafish model of PD. Mitochondrial morphology was evaluated in DA neurons and muscle fibers using immunolabeling and transgenic lines, respectively. We observed diminished mitochondrial area in DA neurons of pink1(−/−) zebrafish, while deletion of mcu restored mitochondrial area. In contrast, the mitochondrial volume in muscle fibers was not restored after inactivation of mcu in pink1(−/−) zebrafish. Mitochondrial calcium overload coupled with depolarization of mitochondrial membrane potential leads to mitochondrial dysfunction in the pink1(−/−) zebrafish model of PD. We used in situ hybridization and immunohistochemical labeling of DA neurons to evaluate the effect of mcu deletion on DA neuronal clusters in the ventral telencephalon of zebrafish brain. We show that DA neurons are rescued after deletion of mcu in pink1(−/−) and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) zebrafish model of PD. Thus, inactivation of mcu is protective in both genetic and chemical models of PD. Our data reveal that regulating mcu function could be an effective therapeutic target in PD pathology. The Company of Biologists Ltd 2019-09-23 /pmc/articles/PMC6826286/ /pubmed/31548178 http://dx.doi.org/10.1242/bio.044347 Text en © 2019. Published by The Company of Biologists Ltd http://creativecommons.org/licenses/by/4.0This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. |
spellingShingle | Research Article Soman, Smijin K. Bazała, Michal Keatinge, Marcus Bandmann, Oliver Kuznicki, Jacek Restriction of mitochondrial calcium overload by mcu inactivation renders a neuroprotective effect in zebrafish models of Parkinson's disease |
title | Restriction of mitochondrial calcium overload by mcu inactivation renders a neuroprotective effect in zebrafish models of Parkinson's disease |
title_full | Restriction of mitochondrial calcium overload by mcu inactivation renders a neuroprotective effect in zebrafish models of Parkinson's disease |
title_fullStr | Restriction of mitochondrial calcium overload by mcu inactivation renders a neuroprotective effect in zebrafish models of Parkinson's disease |
title_full_unstemmed | Restriction of mitochondrial calcium overload by mcu inactivation renders a neuroprotective effect in zebrafish models of Parkinson's disease |
title_short | Restriction of mitochondrial calcium overload by mcu inactivation renders a neuroprotective effect in zebrafish models of Parkinson's disease |
title_sort | restriction of mitochondrial calcium overload by mcu inactivation renders a neuroprotective effect in zebrafish models of parkinson's disease |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826286/ https://www.ncbi.nlm.nih.gov/pubmed/31548178 http://dx.doi.org/10.1242/bio.044347 |
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