DNAJB6b-enriched small extracellular vesicles decrease polyglutamine aggregation in in vitro and in vivo models of Huntington disease

Bhagyashree S Joshi; Sameh A Youssef; Reinier Bron; Alain de Bruin; Harm H Kampinga; Inge S Zuhorn

doi:10.1016/j.isci.2021.103282

DNAJB6b-enriched small extracellular vesicles decrease polyglutamine aggregation in in vitro and in vivo models of Huntington disease

iScience. 2021 Oct 14;24(11):103282. doi: 10.1016/j.isci.2021.103282. eCollection 2021 Nov 19.

Authors

Bhagyashree S Joshi¹, Sameh A Youssef^{2

3}, Reinier Bron¹, Alain de Bruin^{2

3}, Harm H Kampinga⁴, Inge S Zuhorn¹

Affiliations

¹ Department of Biomedical Engineering, University of Groningen, University Medical Center Groningen, A. Deusinglaan 1, 9713 AV Groningen, the Netherlands.
² Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, the Netherlands.
³ Department of Molecular Genetics, Department of Pediatrics, University Medical Center Groningen, Groningen, the Netherlands.
⁴ Department of Biomedical Sciences of Cells and Systems, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Abstract

Huntington disease (HD) is a devastating neurodegenerative disorder characterized by aggregation of huntingtin (HTT) protein containing expanded polyglutamine (polyQ) tracts. DNAJB6, a member of the DNAJ chaperone family, was reported to efficiently inhibit polyQ aggregation in vitro, in cell models, and in vivo in flies, xenopus, and mice. For the delivery of exogenous DNAJB6 to the brain, the DNAJB6 needs to be protected against (enzymatic) degradation and show good penetration into brain tissue. Here, we tested the potential of small extracellular vesicles (sEVs) derived from neural stem cells (NSCs) for delivery of DNAJB6 as anti-amyloidogenic cargo. Administration of sEVs isolated from DNAJB6-overexpressing cells to cells expressing expanded polyQ tracts suppressed HTT aggregation. Furthermore, intrathecal injection of DNAJB6-enriched sEVs into R6/2 transgenic HD mice significantly reduced mutant HTT aggregation in the brain. Taken together, our data suggest that sEV-mediated molecular chaperone delivery may hold potential to delay disease onset in HD.

Keywords: Cell biology; Molecular neuroscience; Molecular physiology.