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Updated: Oct 14, 2025
Fractionation for Resolution of Soluble and Insoluble Huntingtin Species
Published on: February 27, 2018
DNAJB6b-enriched small extracellular vesicles decrease polyglutamine aggregation in in vitro and in vivo models of
Bhagyashree S Joshi1, Sameh A Youssef2,3, Reinier Bron1
1Department of Biomedical Engineering, University of Groningen, University Medical Center Groningen, A. Deusinglaan 1, 9713 AV Groningen, the Netherlands.
Insights
Neural stem cell-derived extracellular vesicles efficiently deliver DNAJB6 to the brain, reducing toxic protein aggregation in Huntington disease models and mice.
Area of Science:
- Neuroscience
- Molecular Biology
- Biochemistry
Background:
- Huntington disease (HD) is a neurodegenerative disorder caused by expanded polyglutamine (polyQ) in the huntingtin (HTT) protein, leading to aggregation.
- DNAJB6, a DNAJ chaperone, effectively inhibits polyQ aggregation in various models.
- Efficient delivery of DNAJB6 to the brain is crucial for therapeutic intervention in HD.
Purpose of the Study:
- To evaluate neural stem cell-derived small extracellular vesicles (sEVs) as a delivery system for DNAJB6 in Huntington disease.
- To assess the efficacy of DNAJB6-loaded sEVs in reducing mutant HTT aggregation in cellular and animal models of HD.
Main Methods:
- Small extracellular vesicles (sEVs) were derived from neural stem cells (NSCs).
- sEVs were engineered to overexpress DNAJB6.
- DNAJB6-enriched sEVs were administered to cells with expanded polyQ tracts and injected intrathecally into R6/2 transgenic HD mice.
Main Results:
- Administration of DNAJB6-overexpressing sEVs suppressed HTT aggregation in cells.
- Intrathecal injection of DNAJB6-enriched sEVs significantly reduced mutant HTT aggregation in the brains of HD mice.
- sEVs demonstrated potential for protecting DNAJB6 from degradation and facilitating brain penetration.
Conclusions:
- sEV-mediated delivery of DNAJB6 shows promise as a therapeutic strategy for Huntington disease.
- This approach may help delay disease onset by reducing toxic protein aggregation in the brain.
- Further research into sEV-based chaperone delivery could offer new avenues for treating neurodegenerative disorders.
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.
