Abstract
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 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.
Highlights
Generation and maintenance of correct protein folding is essential for proper functioning of proteins and key to prevent accumulation of protein aggregates that may gain toxic functions, eventually resulting in cellular dysfunction or cell death (Balchin et al, 2016; Jahn and Radford, 2005)
SUMMARY Huntington disease (HD) is a devastating neurodegenerative disorder characterized by aggregation of huntingtin (HTT) protein containing expanded polyglutamine tracts
We tested the potential of small extracellular vesicles derived from neural stem cells (NSCs) for delivery of DNAJB6 as anti-amyloidogenic cargo
Summary
Generation and maintenance of correct protein folding is essential for proper functioning of proteins and key to prevent accumulation of protein aggregates that may gain toxic functions, eventually resulting in cellular dysfunction or cell death (Balchin et al, 2016; Jahn and Radford, 2005). The expanded polyQ-containing Htt protein has an increased aggregation propensity, which is proportional to the length of the repeat and inversely correlated to the age of onset of the progressive degeneration of neurons in specific brain areas (Takeuchi and Nagai, 2017). Several molecular chaperones, especially those belonging to the co-chaperone family of DNAJ proteins, e.g. DNAJB2 (Howarth et al, 2007) and DNAJB6 (Chai et al, 1999; Kakkar et al, 2016; Labbadia et al, 2012; Takeuchi et al, 2015; Warrick et al, 1999), were found to be effective in reducing polyQ aggregation and to delay the onset of disease in transgenic mouse models. DNAJB6 is among the most powerful modifiers of polyQ aggregation in vitro and in vivo (Bason et al, 2019)
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