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标题：DNAJB6b-enriched small extracellular vesicles decrease polyglutamine aggregation in in vitro and in vivo models of Huntington disease
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作者：Bhagyashree S. Joshi ; Sameh A. Youssef ; Reinier Bron 等
期刊名称：iScience
印刷版ISSN：2589-0042
出版年度：2021
卷号：24
期号：11
页码：1-19
DOI：10.1016/j.isci.2021.103282
语种：English
出版社：Elsevier
摘要：SummaryHuntington 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 aggregationin vitro, in cell models, andin vivoin 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.Graphical abstractDisplay OmittedHighlights•Passive and active loading of neural-stem-cell-derived sEVs with DNAJB6 chaperone•DNAJB6-sEVs suppressed polyQ aggregation in anin vitromodel of Huntington disease•GFP-DNAJB6-sEVs reduced Huntingtin (HTT) aggregation in the striatum of R6/2 HD miceCell biology; Molecular neuroscience; Molecular physiology