NCS1 overexpression restored mitochondrial activity and behavioral alterations in a zebrafish model of Wolfram syndrome
Wolfram syndrome (WS) is a rare neurodegenerative disease resulting in deafness, optic atrophy, diabetes, and neurological disorders. Currently, no treatment is available for patients. The mutated gene, WFS1, encodes an endoplasmic reticulum (ER) protein, Wolframin. We previously reported that Wolfr...
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| Format: | Article |
| Language: | English |
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Elsevier
2022-12-01
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| Series: | Molecular Therapy: Methods & Clinical Development |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2329050122001450 |
| _version_ | 1798029117650632704 |
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| author | Lucie Crouzier Elodie M. Richard Camille Diez Morgane Denus Amandine Peyrel Hala Alzaeem Nicolas Cubedo Thomas Delaunay Tangui Maurice Benjamin Delprat |
| author_facet | Lucie Crouzier Elodie M. Richard Camille Diez Morgane Denus Amandine Peyrel Hala Alzaeem Nicolas Cubedo Thomas Delaunay Tangui Maurice Benjamin Delprat |
| author_sort | Lucie Crouzier |
| collection | DOAJ |
| description | Wolfram syndrome (WS) is a rare neurodegenerative disease resulting in deafness, optic atrophy, diabetes, and neurological disorders. Currently, no treatment is available for patients. The mutated gene, WFS1, encodes an endoplasmic reticulum (ER) protein, Wolframin. We previously reported that Wolframin regulated the ER-mitochondria Ca2+ transfer and mitochondrial activity by protecting NCS1 from degradation in patients’ fibroblasts. We relied on a zebrafish model of WS, the wfs1abKO line, to analyze the functional and behavioral impact of NCS1 overexpression as a novel therapeutic strategy. The wfs1abKO line showed an increased locomotion in the visual motor and touch-escape responses. The absence of wfs1 did not impair the cellular unfolded protein response, in basal or tunicamycin-induced ER stress conditions. In contrast, metabolic analysis showed an increase in mitochondrial respiration in wfs1abKO larvae. Interestingly, overexpression of NCS1 using mRNA injection restored the alteration of mitochondrial respiration and hyperlocomotion. Taken together, these data validated the wfs1abKO zebrafish line as a pertinent experimental model of WS and confirmed the therapeutic potential of NCS1. The wfs1abKO line therefore appeared as an efficient model to identify novel therapeutic strategies, such as gene or pharmacological therapies targeting NCS1 that will correct or block WS symptoms. |
| first_indexed | 2024-04-11T19:19:08Z |
| format | Article |
| id | doaj.art-8a0f00345eee450bbc8aff2f87918237 |
| institution | Directory Open Access Journal |
| issn | 2329-0501 |
| language | English |
| last_indexed | 2024-04-11T19:19:08Z |
| publishDate | 2022-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Methods & Clinical Development |
| spelling | doaj.art-8a0f00345eee450bbc8aff2f879182372022-12-22T04:07:21ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012022-12-0127295308NCS1 overexpression restored mitochondrial activity and behavioral alterations in a zebrafish model of Wolfram syndromeLucie Crouzier0Elodie M. Richard1Camille Diez2Morgane Denus3Amandine Peyrel4Hala Alzaeem5Nicolas Cubedo6Thomas Delaunay7Tangui Maurice8Benjamin Delprat9MMDN, Univ Montpellier, EPHE, INSERM, Montpellier, France.MMDN, Univ Montpellier, EPHE, INSERM, Montpellier, France.MMDN, Univ Montpellier, EPHE, INSERM, Montpellier, France.MMDN, Univ Montpellier, EPHE, INSERM, Montpellier, France.MMDN, Univ Montpellier, EPHE, INSERM, Montpellier, France.MMDN, Univ Montpellier, EPHE, INSERM, Montpellier, France.MMDN, Univ Montpellier, EPHE, INSERM, Montpellier, France.IES, University Montpellier, CNRS, Montpellier, FranceMMDN, Univ Montpellier, EPHE, INSERM, Montpellier, France.MMDN, Univ Montpellier, EPHE, INSERM, Montpellier, France.; Corresponding author Dr B. Delprat, MMDN, Université de Montpellier, Campus Triolet, CC105, place Eugène Bataillon, 34095, Montpellier cedex 5, France.Wolfram syndrome (WS) is a rare neurodegenerative disease resulting in deafness, optic atrophy, diabetes, and neurological disorders. Currently, no treatment is available for patients. The mutated gene, WFS1, encodes an endoplasmic reticulum (ER) protein, Wolframin. We previously reported that Wolframin regulated the ER-mitochondria Ca2+ transfer and mitochondrial activity by protecting NCS1 from degradation in patients’ fibroblasts. We relied on a zebrafish model of WS, the wfs1abKO line, to analyze the functional and behavioral impact of NCS1 overexpression as a novel therapeutic strategy. The wfs1abKO line showed an increased locomotion in the visual motor and touch-escape responses. The absence of wfs1 did not impair the cellular unfolded protein response, in basal or tunicamycin-induced ER stress conditions. In contrast, metabolic analysis showed an increase in mitochondrial respiration in wfs1abKO larvae. Interestingly, overexpression of NCS1 using mRNA injection restored the alteration of mitochondrial respiration and hyperlocomotion. Taken together, these data validated the wfs1abKO zebrafish line as a pertinent experimental model of WS and confirmed the therapeutic potential of NCS1. The wfs1abKO line therefore appeared as an efficient model to identify novel therapeutic strategies, such as gene or pharmacological therapies targeting NCS1 that will correct or block WS symptoms.http://www.sciencedirect.com/science/article/pii/S2329050122001450Wolfram syndromeendoplasmic reticulum stressmitochondriazebrafish larvaeNCS1 |
| spellingShingle | Lucie Crouzier Elodie M. Richard Camille Diez Morgane Denus Amandine Peyrel Hala Alzaeem Nicolas Cubedo Thomas Delaunay Tangui Maurice Benjamin Delprat NCS1 overexpression restored mitochondrial activity and behavioral alterations in a zebrafish model of Wolfram syndrome Molecular Therapy: Methods & Clinical Development Wolfram syndrome endoplasmic reticulum stress mitochondria zebrafish larvae NCS1 |
| title | NCS1 overexpression restored mitochondrial activity and behavioral alterations in a zebrafish model of Wolfram syndrome |
| title_full | NCS1 overexpression restored mitochondrial activity and behavioral alterations in a zebrafish model of Wolfram syndrome |
| title_fullStr | NCS1 overexpression restored mitochondrial activity and behavioral alterations in a zebrafish model of Wolfram syndrome |
| title_full_unstemmed | NCS1 overexpression restored mitochondrial activity and behavioral alterations in a zebrafish model of Wolfram syndrome |
| title_short | NCS1 overexpression restored mitochondrial activity and behavioral alterations in a zebrafish model of Wolfram syndrome |
| title_sort | ncs1 overexpression restored mitochondrial activity and behavioral alterations in a zebrafish model of wolfram syndrome |
| topic | Wolfram syndrome endoplasmic reticulum stress mitochondria zebrafish larvae NCS1 |
| url | http://www.sciencedirect.com/science/article/pii/S2329050122001450 |
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