Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
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
_version_ 1784601551284731904
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
work_keys_str_mv AT darghulamhassan gapdhcontrolsextracellularvesiclebiogenesisandenhancesthetherapeuticpotentialofevmediatedsirnadeliverytothebrain
AT mendesclaudiac gapdhcontrolsextracellularvesiclebiogenesisandenhancesthetherapeuticpotentialofevmediatedsirnadeliverytothebrain
AT kuanweili gapdhcontrolsextracellularvesiclebiogenesisandenhancesthetherapeuticpotentialofevmediatedsirnadeliverytothebrain
AT specialealfinaa gapdhcontrolsextracellularvesiclebiogenesisandenhancesthetherapeuticpotentialofevmediatedsirnadeliverytothebrain
AT conceicaomariana gapdhcontrolsextracellularvesiclebiogenesisandenhancesthetherapeuticpotentialofevmediatedsirnadeliverytothebrain
AT gorgensandre gapdhcontrolsextracellularvesiclebiogenesisandenhancesthetherapeuticpotentialofevmediatedsirnadeliverytothebrain
AT uliyakinainna gapdhcontrolsextracellularvesiclebiogenesisandenhancesthetherapeuticpotentialofevmediatedsirnadeliverytothebrain
AT lobomiguelj gapdhcontrolsextracellularvesiclebiogenesisandenhancesthetherapeuticpotentialofevmediatedsirnadeliverytothebrain
AT limwooif gapdhcontrolsextracellularvesiclebiogenesisandenhancesthetherapeuticpotentialofevmediatedsirnadeliverytothebrain
AT elandaloussisamir gapdhcontrolsextracellularvesiclebiogenesisandenhancesthetherapeuticpotentialofevmediatedsirnadeliverytothebrain
AT magerimre gapdhcontrolsextracellularvesiclebiogenesisandenhancesthetherapeuticpotentialofevmediatedsirnadeliverytothebrain
AT robertsthomasc gapdhcontrolsextracellularvesiclebiogenesisandenhancesthetherapeuticpotentialofevmediatedsirnadeliverytothebrain
AT barkerrogera gapdhcontrolsextracellularvesiclebiogenesisandenhancesthetherapeuticpotentialofevmediatedsirnadeliverytothebrain
AT goberdhandeborahci gapdhcontrolsextracellularvesiclebiogenesisandenhancesthetherapeuticpotentialofevmediatedsirnadeliverytothebrain
AT wilsonclive gapdhcontrolsextracellularvesiclebiogenesisandenhancesthetherapeuticpotentialofevmediatedsirnadeliverytothebrain
AT woodmatthewja gapdhcontrolsextracellularvesiclebiogenesisandenhancesthetherapeuticpotentialofevmediatedsirnadeliverytothebrain