GAPDH controls extracellular vesicle biogenesis and enhances the therapeutic potential of EV mediated siRNA delivery to the brain
Authors
Dar, Ghulam Hassan
Mendes, Cláudia C.
Kuan, Wei-Li
Conceição, Mariana
Uliyakina, Inna
Lobo, Miguel J.
Barker, Roger A.
Wilson, Clive
Publication Date
2021-11-18Journal Title
Nature Communications
Publisher
Nature Publishing Group UK
Volume
12
Issue
1
Language
en
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Dar, G. H., Mendes, C. C., Kuan, W., Speciale, A. A., Conceição, M., Görgens, A., Uliyakina, I., et al. (2021). GAPDH controls extracellular vesicle biogenesis and enhances the therapeutic potential of EV mediated siRNA delivery to the brain. Nature Communications, 12 (1) https://doi.org/10.1038/s41467-021-27056-3
Abstract
Abstract: 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.
Keywords
Article, /631/61/391/3932, /631/80/86/820, /13, /13/89, /14, /38, /42, /42/89, /59, /59/5, /64, /64/60, article
Sponsorship
RCUK | Medical Research Council (MRC) (MR/M007715/1)
Identifiers
s41467-021-27056-3, 27056
External DOI: https://doi.org/10.1038/s41467-021-27056-3
This record's URL: https://www.repository.cam.ac.uk/handle/1810/332029
Rights
Licence:
http://creativecommons.org/licenses/by/4.0/
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