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GAPDH controls extracellular vesicle biogenesis and enhances the therapeutic potential of EV mediated siRNA delivery to the brain

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dc.contributor.authorDar, Ghulam Hassan
dc.contributor.authorMendes, Cláudia C.
dc.contributor.authorKuan, Wei-Li
dc.contributor.authorSpeciale, Alfina A.
dc.contributor.authorConceição, Mariana
dc.contributor.authorGörgens, André
dc.contributor.authorUliyakina, Inna
dc.contributor.authorLobo, Miguel J.
dc.contributor.authorLim, Wooi F.
dc.contributor.authorEL Andaloussi, Samir
dc.contributor.authorMäger, Imre
dc.contributor.authorRoberts, Thomas C.
dc.contributor.authorBarker, Roger A.
dc.contributor.authorGoberdhan, Deborah C. I.
dc.contributor.authorWilson, Clive
dc.contributor.authorWood, Matthew J. A.
dc.contributor.orcidSpeciale, Alfina A. [0000-0001-9728-254X]
dc.contributor.orcidGörgens, André [0000-0001-9198-0857]
dc.contributor.orcidLim, Wooi F. [0000-0002-1238-3040]
dc.contributor.orcidEL Andaloussi, Samir [0000-0003-4468-9113]
dc.contributor.orcidMäger, Imre [0000-0003-2242-7227]
dc.contributor.orcidRoberts, Thomas C. [0000-0002-3313-7631]
dc.contributor.orcidGoberdhan, Deborah C. I. [0000-0003-0645-6714]
dc.contributor.orcidWood, Matthew J. A. [0000-0002-5436-6011]
dc.date.accessioned2022-01-05T10:49:00Z
dc.date.available2022-01-05T10:49:00Z
dc.date.issued2021-11-18
dc.date.submitted2020-03-09
dc.date.updated2022-01-05T10:48:59Z
dc.description.abstractAbstract: 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.
dc.identifier.doi10.17863/CAM.79454
dc.identifier.eissn2041-1723
dc.identifier.others41467-021-27056-3
dc.identifier.other27056
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/332006
dc.languageen
dc.publisherNature Publishing Group UK
dc.subjectArticle
dc.subject/631/61/391/3932
dc.subject/631/80/86/820
dc.subject/13
dc.subject/13/89
dc.subject/14
dc.subject/38
dc.subject/42
dc.subject/42/89
dc.subject/59
dc.subject/59/5
dc.subject/64
dc.subject/64/60
dc.subjectarticle
dc.titleGAPDH controls extracellular vesicle biogenesis and enhances the therapeutic potential of EV mediated siRNA delivery to the brain
dc.typeArticle
dcterms.dateAccepted2021-10-17
prism.issueIdentifier1
prism.publicationNameNature Communications
prism.volume12
pubs.funder-project-idRCUK | Medical Research Council (MRC) (MR/M007715/1)
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1038/s41467-021-27056-3

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