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

Published version
Peer-reviewed

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Authors

Dar, Ghulam Hassan 
Mendes, Cláudia C. 
Kuan, Wei-Li 
Speciale, Alfina A.  ORCID logo  https://orcid.org/0000-0001-9728-254X
Conceição, Mariana 

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.

Description

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

Journal Title

Nature Communications

Conference Name

Journal ISSN

2041-1723

Volume Title

12

Publisher

Nature Publishing Group UK
Sponsorship
RCUK | Medical Research Council (MRC) (MR/M007715/1)