The Nitric Oxide Donor, S-Nitrosoglutathione, Rescues Peroxisome Number and Activity Defects in PEX1G843D Mild Zellweger Syndrome Fibroblasts

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

doi:10.3389/fcell.2021.714710

The Nitric Oxide Donor, S-Nitrosoglutathione, Rescues Peroxisome Number and Activity Defects in PEX1G843D Mild Zellweger Syndrome Fibroblasts

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

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4 Citas (Scopus)

Resumen

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.

Idioma original	English
Número de artículo	714710
Publicación	Frontiers in Cell and Developmental Biology
Volumen	9
DOI	https://doi.org/10.3389/fcell.2021.714710
Estado	Published - ago. 9 2021

Nota bibliográfica

Funding Information:
We thank Nancy Braverman (McGill University) for advice and for providing wild-type human fibroblasts and PEX1G843D mutant human fibroblasts. Lipid profiling was done at the Lipidomics Core Facility at the University of Alberta, which is supported by funding from the Faculty of Medicine & Dentistry and the Women and Children’s Health Research Institute, University of Alberta. The compound screen was performed at the High Content Analysis Core, University of Alberta, Faculty of Medicine & Dentistry. Funding. This work was funded by a Collaborative Research Innovation Opportunities grant from Alberta Innovates Health Solutions to RR and AS; a Foundation Grant from the Canadian Institutes of Health Research (CIHR) to RR; a Discovery Grant from the Natural Sciences and Engineering Research Council of Canada to FD (RGPIN/04083-2019); and an Operating Grant from the CIHR (PJT-169179) to FD. We thank the Dalhousie Medical Research Foundation and the Beatrice Hunter Cancer Institute for supporting CMW.

Funding Information:
This work was funded by a Collaborative Research Innovation Opportunities grant from Alberta Innovates Health Solutions to RR and AS; a Foundation Grant from the Canadian Institutes of Health Research (CIHR) to RR; a Discovery Grant from the Natural Sciences and Engineering Research Council of Canada to FD (RGPIN/04083-2019); and an Operating Grant from the CIHR (PJT-169179) to FD. We thank the Dalhousie Medical Research Foundation and the Beatrice Hunter Cancer Institute for supporting CMW.

Funding Information:
We thank Nancy Braverman (McGill University) for advice and for providing wild-type human fibroblasts and PEX1G843D mutant human fibroblasts. Lipid profiling was done at the Lipidomics Core Facility at the University of Alberta, which is supported by funding from the Faculty of Medicine & Dentistry and the Women and Children’s Health Research Institute, University of Alberta. The compound screen was performed at the High Content Analysis Core, University of Alberta, Faculty of Medicine & Dentistry.

Publisher Copyright:
© Copyright © 2021 Liu, Weaver, Sen, Eitzen, Simmonds, Linchieh, Lurette, Hebert-Chatelain, Rachubinski and Di Cara.

ASJC Scopus Subject Areas

Developmental Biology
Cell Biology

PubMed: MeSH publication types

Journal Article

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10.3389/fcell.2021.714710

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Liu, Y., Weaver, C. M., Sen, Y., Eitzen, G., Simmonds, A. J., Linchieh, L., Lurette, O., Hebert-Chatelain, E., Rachubinski, R. A., & Di Cara, F. (2021). The Nitric Oxide Donor, S-Nitrosoglutathione, Rescues Peroxisome Number and Activity Defects in PEX1G843D Mild Zellweger Syndrome Fibroblasts. Frontiers in Cell and Developmental Biology, 9, Artículo 714710. https://doi.org/10.3389/fcell.2021.714710

Liu, Y, Weaver, CM, Sen, Y, Eitzen, G, Simmonds, AJ, Linchieh, L, Lurette, O, Hebert-Chatelain, E, Rachubinski, RA & Di Cara, F 2021, 'The Nitric Oxide Donor, S-Nitrosoglutathione, Rescues Peroxisome Number and Activity Defects in PEX1G843D Mild Zellweger Syndrome Fibroblasts', Frontiers in Cell and Developmental Biology, vol. 9, 714710. https://doi.org/10.3389/fcell.2021.714710

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title = "The Nitric Oxide Donor, S-Nitrosoglutathione, Rescues Peroxisome Number and Activity Defects in PEX1G843D Mild Zellweger Syndrome Fibroblasts",

abstract = "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.",

author = "Yidi Liu and Weaver, {Ceileigh M.} and Yarina Sen and Gary Eitzen and Simmonds, {Andrew J.} and Lilliana Linchieh and Olivier Lurette and Etienne Hebert-Chatelain and Rachubinski, {Richard A.} and {Di Cara}, Francesca",

note = "Funding Information: We thank Nancy Braverman (McGill University) for advice and for providing wild-type human fibroblasts and PEX1G843D mutant human fibroblasts. Lipid profiling was done at the Lipidomics Core Facility at the University of Alberta, which is supported by funding from the Faculty of Medicine & Dentistry and the Women and Children{\textquoteright}s Health Research Institute, University of Alberta. The compound screen was performed at the High Content Analysis Core, University of Alberta, Faculty of Medicine & Dentistry. Funding. This work was funded by a Collaborative Research Innovation Opportunities grant from Alberta Innovates Health Solutions to RR and AS; a Foundation Grant from the Canadian Institutes of Health Research (CIHR) to RR; a Discovery Grant from the Natural Sciences and Engineering Research Council of Canada to FD (RGPIN/04083-2019); and an Operating Grant from the CIHR (PJT-169179) to FD. We thank the Dalhousie Medical Research Foundation and the Beatrice Hunter Cancer Institute for supporting CMW. Funding Information: This work was funded by a Collaborative Research Innovation Opportunities grant from Alberta Innovates Health Solutions to RR and AS; a Foundation Grant from the Canadian Institutes of Health Research (CIHR) to RR; a Discovery Grant from the Natural Sciences and Engineering Research Council of Canada to FD (RGPIN/04083-2019); and an Operating Grant from the CIHR (PJT-169179) to FD. We thank the Dalhousie Medical Research Foundation and the Beatrice Hunter Cancer Institute for supporting CMW. Funding Information: We thank Nancy Braverman (McGill University) for advice and for providing wild-type human fibroblasts and PEX1G843D mutant human fibroblasts. Lipid profiling was done at the Lipidomics Core Facility at the University of Alberta, which is supported by funding from the Faculty of Medicine & Dentistry and the Women and Children{\textquoteright}s Health Research Institute, University of Alberta. The compound screen was performed at the High Content Analysis Core, University of Alberta, Faculty of Medicine & Dentistry. Publisher Copyright: {\textcopyright} Copyright {\textcopyright} 2021 Liu, Weaver, Sen, Eitzen, Simmonds, Linchieh, Lurette, Hebert-Chatelain, Rachubinski and Di Cara.",

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AU - Sen, Yarina

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The Nitric Oxide Donor, S-Nitrosoglutathione, Rescues Peroxisome Number and Activity Defects in PEX1G843D Mild Zellweger Syndrome Fibroblasts

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ASJC Scopus Subject Areas

PubMed: MeSH publication types

ODS de las Naciones Unidas

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