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GAPDH controls extracellular vesicle biogenesis and enhances the therapeutic potential of EV mediated siRNA delivery to the brain
Extracellular vesicles (EVs) are biological nanoparticles with important roles in intercellular communication, and potential as drug delivery vehicles. Here we demonstrate a role for the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in EV assembly and secretion. We observe high...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8602309/ https://www.ncbi.nlm.nih.gov/pubmed/34795295 http://dx.doi.org/10.1038/s41467-021-27056-3 |
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author | Dar, Ghulam Hassan Mendes, Cláudia C. Kuan, Wei-Li Speciale, Alfina A. Conceição, Mariana Görgens, André Uliyakina, Inna Lobo, Miguel J. Lim, Wooi F. EL Andaloussi, Samir Mäger, Imre Roberts, Thomas C. Barker, Roger A. Goberdhan, Deborah C. I. Wilson, Clive Wood, Matthew J. A. |
author_facet | Dar, Ghulam Hassan Mendes, Cláudia C. Kuan, Wei-Li Speciale, Alfina A. Conceição, Mariana Görgens, André Uliyakina, Inna Lobo, Miguel J. Lim, Wooi F. EL Andaloussi, Samir Mäger, Imre Roberts, Thomas C. Barker, Roger A. Goberdhan, Deborah C. I. Wilson, Clive Wood, Matthew J. A. |
author_sort | Dar, Ghulam Hassan |
collection | PubMed |
description | Extracellular vesicles (EVs) are biological nanoparticles with important roles in intercellular communication, and potential as drug delivery vehicles. Here we demonstrate a role for the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in EV assembly and secretion. We observe high levels of GAPDH binding to the outer surface of EVs via a phosphatidylserine binding motif (G58), which promotes extensive EV clustering. Further studies in a Drosophila EV biogenesis model reveal that GAPDH is required for the normal generation of intraluminal vesicles in endosomal compartments, and promotes vesicle clustering. Fusion of the GAPDH-derived G58 peptide to dsRNA-binding motifs enables highly efficient loading of small interfering RNA (siRNA) onto the EV surface. Such vesicles efficiently deliver siRNA to multiple anatomical regions of the brain in a Huntington’s disease mouse model after systemic injection, resulting in silencing of the huntingtin gene in different regions of the brain. |
format | Online Article Text |
id | pubmed-8602309 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-86023092021-11-19 GAPDH controls extracellular vesicle biogenesis and enhances the therapeutic potential of EV mediated siRNA delivery to the brain Dar, Ghulam Hassan Mendes, Cláudia C. Kuan, Wei-Li Speciale, Alfina A. Conceição, Mariana Görgens, André Uliyakina, Inna Lobo, Miguel J. Lim, Wooi F. EL Andaloussi, Samir Mäger, Imre Roberts, Thomas C. Barker, Roger A. Goberdhan, Deborah C. I. Wilson, Clive Wood, Matthew J. A. Nat Commun Article Extracellular vesicles (EVs) are biological nanoparticles with important roles in intercellular communication, and potential as drug delivery vehicles. Here we demonstrate a role for the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in EV assembly and secretion. We observe high levels of GAPDH binding to the outer surface of EVs via a phosphatidylserine binding motif (G58), which promotes extensive EV clustering. Further studies in a Drosophila EV biogenesis model reveal that GAPDH is required for the normal generation of intraluminal vesicles in endosomal compartments, and promotes vesicle clustering. Fusion of the GAPDH-derived G58 peptide to dsRNA-binding motifs enables highly efficient loading of small interfering RNA (siRNA) onto the EV surface. Such vesicles efficiently deliver siRNA to multiple anatomical regions of the brain in a Huntington’s disease mouse model after systemic injection, resulting in silencing of the huntingtin gene in different regions of the brain. Nature Publishing Group UK 2021-11-18 /pmc/articles/PMC8602309/ /pubmed/34795295 http://dx.doi.org/10.1038/s41467-021-27056-3 Text en © The Author(s) 2021, corrected publication 2021 https://creativecommons.org/licenses/by/4.0/Open Access This 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Dar, Ghulam Hassan Mendes, Cláudia C. Kuan, Wei-Li Speciale, Alfina A. Conceição, Mariana Görgens, André Uliyakina, Inna Lobo, Miguel J. Lim, Wooi F. EL Andaloussi, Samir Mäger, Imre Roberts, Thomas C. Barker, Roger A. Goberdhan, Deborah C. I. Wilson, Clive Wood, Matthew J. A. GAPDH controls extracellular vesicle biogenesis and enhances the therapeutic potential of EV mediated siRNA delivery to the brain |
title | GAPDH controls extracellular vesicle biogenesis and enhances the therapeutic potential of EV mediated siRNA delivery to the brain |
title_full | GAPDH controls extracellular vesicle biogenesis and enhances the therapeutic potential of EV mediated siRNA delivery to the brain |
title_fullStr | GAPDH controls extracellular vesicle biogenesis and enhances the therapeutic potential of EV mediated siRNA delivery to the brain |
title_full_unstemmed | GAPDH controls extracellular vesicle biogenesis and enhances the therapeutic potential of EV mediated siRNA delivery to the brain |
title_short | GAPDH controls extracellular vesicle biogenesis and enhances the therapeutic potential of EV mediated siRNA delivery to the brain |
title_sort | gapdh controls extracellular vesicle biogenesis and enhances the therapeutic potential of ev mediated sirna delivery to the brain |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8602309/ https://www.ncbi.nlm.nih.gov/pubmed/34795295 http://dx.doi.org/10.1038/s41467-021-27056-3 |
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