The Nitric Oxide Donor, S-Nitrosoglutathione, Rescues Peroxisome Number and Activity Defects in PEX1G843D Mild Zellweger Syndrome Fibroblasts
Peroxisome biogenesis disorders (PBDs) are a group of metabolic developmental diseases caused by mutations in one or more genes encoding peroxisomal proteins. Zellweger syndrome spectrum (PBD-ZSS) results from metabolic dysfunction caused by damaged or non-functional peroxisomes and manifests as a m...
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Frontiers Media S.A.
2021-08-01
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| Series: | Frontiers in Cell and Developmental Biology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2021.714710/full |
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| author | Yidi Liu Ceileigh M. Weaver Yarina Sen Gary Eitzen Andrew J. Simmonds Lilliana Linchieh Olivier Lurette Etienne Hebert-Chatelain Richard A. Rachubinski Francesca Di Cara |
| author_facet | Yidi Liu Ceileigh M. Weaver Yarina Sen Gary Eitzen Andrew J. Simmonds Lilliana Linchieh Olivier Lurette Etienne Hebert-Chatelain Richard A. Rachubinski Francesca Di Cara |
| author_sort | Yidi Liu |
| collection | DOAJ |
| description | Peroxisome biogenesis disorders (PBDs) are a group of metabolic developmental diseases caused by mutations in one or more genes encoding peroxisomal proteins. Zellweger syndrome spectrum (PBD-ZSS) results from metabolic dysfunction caused by damaged or non-functional peroxisomes and manifests as a multi-organ syndrome with significant morbidity and mortality for which there is no current drug therapy. Mild PBD-ZSS patients can exhibit a more progressive disease course and could benefit from the identification of drugs to improve the quality of life and extend the lifespan of affected individuals. Our study used a high-throughput screen of FDA-approved compounds to identify compounds that improve peroxisome function and biogenesis in human fibroblast cells carrying the mild PBD-ZSS variant, PEX1G843D. Our screen identified the nitrogen oxide donor, S-nitrosoglutathione (GSNO), as a potential therapeutic for this mild form of PBD-ZSS. Further biochemical characterization showed that GSNO enhances both peroxisome number and function in PEX1G843D mutant fibroblasts and leads to increased survival and longer lifespan in an in vivo humanized Drosophila model carrying the PEX1G843D mutation. GSNO is therefore a strong candidate to be translated to clinical trials as a potential therapeutic for mild PBD-ZSS. |
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| issn | 2296-634X |
| language | English |
| last_indexed | 2024-12-13T19:25:32Z |
| publishDate | 2021-08-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj.art-a3e32b64330e48c1a3b80326f3cf13f02022-12-21T23:34:03ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2021-08-01910.3389/fcell.2021.714710714710The Nitric Oxide Donor, S-Nitrosoglutathione, Rescues Peroxisome Number and Activity Defects in PEX1G843D Mild Zellweger Syndrome FibroblastsYidi Liu0Ceileigh M. Weaver1Yarina Sen2Gary Eitzen3Andrew J. Simmonds4Lilliana Linchieh5Olivier Lurette6Etienne Hebert-Chatelain7Richard A. Rachubinski8Francesca Di Cara9Department of Cell Biology, University of Alberta, Edmonton, AB, CanadaDepartment of Microbiology and Immunology, IWK Research Centre, Dalhousie University, Halifax, NS, CanadaDepartment of Cell Biology, University of Alberta, Edmonton, AB, CanadaDepartment of Cell Biology, University of Alberta, Edmonton, AB, CanadaDepartment of Cell Biology, University of Alberta, Edmonton, AB, CanadaDepartment of Cell Biology, University of Alberta, Edmonton, AB, CanadaDepartment of Biology, University of Moncton, Moncton, NB, CanadaDepartment of Biology, University of Moncton, Moncton, NB, CanadaDepartment of Cell Biology, University of Alberta, Edmonton, AB, CanadaDepartment of Microbiology and Immunology, IWK Research Centre, Dalhousie University, Halifax, NS, CanadaPeroxisome biogenesis disorders (PBDs) are a group of metabolic developmental diseases caused by mutations in one or more genes encoding peroxisomal proteins. Zellweger syndrome spectrum (PBD-ZSS) results from metabolic dysfunction caused by damaged or non-functional peroxisomes and manifests as a multi-organ syndrome with significant morbidity and mortality for which there is no current drug therapy. Mild PBD-ZSS patients can exhibit a more progressive disease course and could benefit from the identification of drugs to improve the quality of life and extend the lifespan of affected individuals. Our study used a high-throughput screen of FDA-approved compounds to identify compounds that improve peroxisome function and biogenesis in human fibroblast cells carrying the mild PBD-ZSS variant, PEX1G843D. Our screen identified the nitrogen oxide donor, S-nitrosoglutathione (GSNO), as a potential therapeutic for this mild form of PBD-ZSS. Further biochemical characterization showed that GSNO enhances both peroxisome number and function in PEX1G843D mutant fibroblasts and leads to increased survival and longer lifespan in an in vivo humanized Drosophila model carrying the PEX1G843D mutation. GSNO is therefore a strong candidate to be translated to clinical trials as a potential therapeutic for mild PBD-ZSS.https://www.frontiersin.org/articles/10.3389/fcell.2021.714710/fullperoxisomePEX1G843D mutationZellweger spectrum disordersS-nitrosoglutathionehigh-throughput screendrug library |
| spellingShingle | Yidi Liu Ceileigh M. Weaver Yarina Sen Gary Eitzen Andrew J. Simmonds Lilliana Linchieh Olivier Lurette Etienne Hebert-Chatelain Richard A. Rachubinski Francesca Di Cara The Nitric Oxide Donor, S-Nitrosoglutathione, Rescues Peroxisome Number and Activity Defects in PEX1G843D Mild Zellweger Syndrome Fibroblasts Frontiers in Cell and Developmental Biology peroxisome PEX1G843D mutation Zellweger spectrum disorders S-nitrosoglutathione high-throughput screen drug library |
| title | The Nitric Oxide Donor, S-Nitrosoglutathione, Rescues Peroxisome Number and Activity Defects in PEX1G843D Mild Zellweger Syndrome Fibroblasts |
| title_full | The Nitric Oxide Donor, S-Nitrosoglutathione, Rescues Peroxisome Number and Activity Defects in PEX1G843D Mild Zellweger Syndrome Fibroblasts |
| title_fullStr | The Nitric Oxide Donor, S-Nitrosoglutathione, Rescues Peroxisome Number and Activity Defects in PEX1G843D Mild Zellweger Syndrome Fibroblasts |
| title_full_unstemmed | The Nitric Oxide Donor, S-Nitrosoglutathione, Rescues Peroxisome Number and Activity Defects in PEX1G843D Mild Zellweger Syndrome Fibroblasts |
| title_short | The Nitric Oxide Donor, S-Nitrosoglutathione, Rescues Peroxisome Number and Activity Defects in PEX1G843D Mild Zellweger Syndrome Fibroblasts |
| title_sort | nitric oxide donor s nitrosoglutathione rescues peroxisome number and activity defects in pex1g843d mild zellweger syndrome fibroblasts |
| topic | peroxisome PEX1G843D mutation Zellweger spectrum disorders S-nitrosoglutathione high-throughput screen drug library |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2021.714710/full |
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