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

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.

SUBMITTER: Joshi BS

PROVIDER: S-EPMC8564107 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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

Joshi Bhagyashree S BS Youssef Sameh A SA Bron Reinier R de Bruin Alain A Kampinga Harm H HH Zuhorn Inge S IS

iScience 20211014 11

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 i ...[more]

PMID: 34755099

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Project description:Aimaliva extracellular vesicles (EVs) serve as a significant reservoir of biomarkers that may be of clinical use in disease diagnosis. Saliva, however, contains EVs of both host- and bacterial- origin. Identifying suitable EVs for disease diagnosis involves enriching host EVs and limiting non-host contamination with effective isolation methods. The objectives of this research were: (1) to evaluate the salivary EVs enrichment in 12 periodontally healthy patients by two different methods: size exclusion chromatography (SEC) and bead-based immunoaffinity capture (EXO-NET®); (2) to analyze the variance expression of inflammatory cytokines in EXO-NET-enriched EVs, comparing individuals with periodontitis (n = 20) to non-periodontitis (n = 12).MethodsWhole unstimulated saliva samples were collected from 12 periodontally healthy and 20 periodontitis patients. EVs were isolated from the 12 non-periodontitis patients using SEC (referred to as SEC-EVs) and EXO-NET (referred to as EXO-NET EVs), after which their total protein content, 37 EV surface markers, and bacterial pathogens expression were compared. Subsequently, the inflammatory cytokines expression levels (interleukin-IL-6, IL-1β, IL-8, and IL-10) in EXO-NET EVs were measured for non-periodontitis and periodontitis.ResultsEXO-NET EVs contained more EV-specific protein and substantially higher expression of EV surface markers (CD9, CD81, CD63), but less pathogenic DNA was detected compared to that in SEC-EVs. Additionally, EXO-NET EVs from periodontitis patients contained higher amounts of IL-6 and IL-8, and decreased IL-10, compared to those from non-periodontitis patients.ConclusionThe findings suggest that immunoaffinity capture (EXO-NET) is a dependable method for salivary EVs enrichment, resulting in a higher yield of host EVs with reduced bacterial DNA detection compared to SEC. Furthermore, the research proposes that immunoaffinity capture enriched EVs can function as biomarkers for periodontitis, demonstrated by an increased expression of proinflammatory cytokines from periodontitis patients.

Project description:BackgroundAlzheimer's disease (AD) is the most common neurodegenerative disorder with clinical presentations of progressive cognitive and memory deterioration. The pathologic hallmarks of AD include tau neurofibrillary tangles and amyloid plaque depositions in the hippocampus and associated neocortex. The neuronal aggregated tau observed in AD cells suggests that the protein folding problem is a major cause of AD. J-domain-containing proteins (JDPs) are the largest family of cochaperones, which play a vital role in specifying and directing HSP70 chaperone functions. JDPs bind substrates and deliver them to HSP70. The association of JDP and HSP70 opens the substrate-binding domain of HSP70 to help the loading of the clients. However, in the initial HSP70 cycle, which JDP delivers tau to the HSP70 system in neuronal cells remains unclear.ResultsWe screened the requirement of a diverse panel of JDPs for preventing tau aggregation in the human neuroblastoma cell line SH-SY5Y by a filter retardation method. Interestingly, knockdown of DNAJB6, one of the JDPs, displayed tau aggregation and overexpression of DNAJB6b, one of the isoforms generated from the DNAJB6 gene by alternative splicing, reduced tau aggregation. Further, the tau bimolecular fluorescence complementation assay confirmed the DNAJB6b-dependent tau clearance. The co-immunoprecipitation and the proximity ligation assay demonstrated the protein-protein interaction between tau and the chaperone-cochaperone complex. The J-domain of DNAJB6b was critical for preventing tau aggregation. Moreover, reduced DNAJB6 expression and increased tau aggregation were detected in an age-dependent manner in immunohistochemical analysis of the hippocampus tissues of a mouse model of tau pathology.ConclusionsIn summary, downregulation of DNAJB6b increases the insoluble form of tau, while overexpression of DNAJB6b reduces tau aggregation. Moreover, DNAJB6b associates with tau. Therefore, this study reveals that DNAJB6b is a direct sensor for its client tau in the HSP70 folding system in neuronal cells, thus helping to prevent AD.

Dataset Information

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

Publications

DNAJB6b-enriched small extracellular vesicles decrease polyglutamine aggregation in <i>in vitro</i> and <i>in vivo</i> models of Huntington disease.

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