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Loss of Drosophila Coq8 results in impaired survival, locomotor deficits and photoreceptor degeneration
Coenzyme Q8A encodes the homologue of yeast coq8, an ATPase that is required for the biosynthesis of Coenzyme Q10, an essential component of the electron transport chain. Mutations in COQ8A in humans result in CoQ10 deficiency, the clinical features of which include early-onset cerebellar ataxia, se...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8827264/ https://www.ncbi.nlm.nih.gov/pubmed/35139868 http://dx.doi.org/10.1186/s13041-022-00900-3 |
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author | Hura, Angelia J. Hawley, Hannah R. Tan, Wei Jun Penny, Rebecca J. Jacobsen, Jessie C. Fitzsimons, Helen L. |
author_facet | Hura, Angelia J. Hawley, Hannah R. Tan, Wei Jun Penny, Rebecca J. Jacobsen, Jessie C. Fitzsimons, Helen L. |
author_sort | Hura, Angelia J. |
collection | PubMed |
description | Coenzyme Q8A encodes the homologue of yeast coq8, an ATPase that is required for the biosynthesis of Coenzyme Q10, an essential component of the electron transport chain. Mutations in COQ8A in humans result in CoQ10 deficiency, the clinical features of which include early-onset cerebellar ataxia, seizures and intellectual disability. The rapid advancement of massively parallel sequencing has resulted in the identification of more than 40 new mutations in COQ8A and functional studies are required to confirm causality and to further research into determining the specific mechanisms through which the mutations result in loss of function. To that end, a Drosophila model of Coq8 deficiency was developed and characterized to determine its appropriateness as a model system to further explore the role of Coq8 in the brain, and for functional characterisation of Coq8 mutations. Pan-neuronal RNAi knockdown of Coq8 was largely lethal, with female escapers displaying severe locomotor deficits. Knockdown of Coq8 in the eye resulted in degeneration of photoreceptors, progressive necrosis and increased generation of reactive oxygen species. Reintroduction of wild-type Coq8 restored normal function, however expression of human wild-type COQ8A exacerbated the eye phenotype, suggesting it was acting as a dominant-negative. This model is therefore informative for investigating the function of Drosophila Coq8, however human COQ8A mutations cannot be assessed as hCOQ8A does not rescue Coq8 deficiency. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13041-022-00900-3. |
format | Online Article Text |
id | pubmed-8827264 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-88272642022-02-10 Loss of Drosophila Coq8 results in impaired survival, locomotor deficits and photoreceptor degeneration Hura, Angelia J. Hawley, Hannah R. Tan, Wei Jun Penny, Rebecca J. Jacobsen, Jessie C. Fitzsimons, Helen L. Mol Brain Micro Report Coenzyme Q8A encodes the homologue of yeast coq8, an ATPase that is required for the biosynthesis of Coenzyme Q10, an essential component of the electron transport chain. Mutations in COQ8A in humans result in CoQ10 deficiency, the clinical features of which include early-onset cerebellar ataxia, seizures and intellectual disability. The rapid advancement of massively parallel sequencing has resulted in the identification of more than 40 new mutations in COQ8A and functional studies are required to confirm causality and to further research into determining the specific mechanisms through which the mutations result in loss of function. To that end, a Drosophila model of Coq8 deficiency was developed and characterized to determine its appropriateness as a model system to further explore the role of Coq8 in the brain, and for functional characterisation of Coq8 mutations. Pan-neuronal RNAi knockdown of Coq8 was largely lethal, with female escapers displaying severe locomotor deficits. Knockdown of Coq8 in the eye resulted in degeneration of photoreceptors, progressive necrosis and increased generation of reactive oxygen species. Reintroduction of wild-type Coq8 restored normal function, however expression of human wild-type COQ8A exacerbated the eye phenotype, suggesting it was acting as a dominant-negative. This model is therefore informative for investigating the function of Drosophila Coq8, however human COQ8A mutations cannot be assessed as hCOQ8A does not rescue Coq8 deficiency. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13041-022-00900-3. BioMed Central 2022-02-09 /pmc/articles/PMC8827264/ /pubmed/35139868 http://dx.doi.org/10.1186/s13041-022-00900-3 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Micro Report Hura, Angelia J. Hawley, Hannah R. Tan, Wei Jun Penny, Rebecca J. Jacobsen, Jessie C. Fitzsimons, Helen L. Loss of Drosophila Coq8 results in impaired survival, locomotor deficits and photoreceptor degeneration |
title | Loss of Drosophila Coq8 results in impaired survival, locomotor deficits and photoreceptor degeneration |
title_full | Loss of Drosophila Coq8 results in impaired survival, locomotor deficits and photoreceptor degeneration |
title_fullStr | Loss of Drosophila Coq8 results in impaired survival, locomotor deficits and photoreceptor degeneration |
title_full_unstemmed | Loss of Drosophila Coq8 results in impaired survival, locomotor deficits and photoreceptor degeneration |
title_short | Loss of Drosophila Coq8 results in impaired survival, locomotor deficits and photoreceptor degeneration |
title_sort | loss of drosophila coq8 results in impaired survival, locomotor deficits and photoreceptor degeneration |
topic | Micro Report |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8827264/ https://www.ncbi.nlm.nih.gov/pubmed/35139868 http://dx.doi.org/10.1186/s13041-022-00900-3 |
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