DNAJB6b-enriched small extracellular vesicles decrease polyglutamine aggregation in in vitro and in vivo models of Huntington disease
Summary: 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 ce...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2021-11-01
|
| Series: | iScience |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004221012517 |
| _version_ | 1818825024490962944 |
|---|---|
| author | Bhagyashree S. Joshi Sameh A. Youssef Reinier Bron Alain de Bruin Harm H. Kampinga Inge S. Zuhorn |
| author_facet | Bhagyashree S. Joshi Sameh A. Youssef Reinier Bron Alain de Bruin Harm H. Kampinga Inge S. Zuhorn |
| author_sort | Bhagyashree S. Joshi |
| collection | DOAJ |
| description | Summary: 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. |
| first_indexed | 2024-12-19T00:05:11Z |
| format | Article |
| id | doaj.art-7e72da794b2c4764b06ad74b280ea482 |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-12-19T00:05:11Z |
| publishDate | 2021-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-7e72da794b2c4764b06ad74b280ea4822022-12-21T20:46:17ZengElsevieriScience2589-00422021-11-012411103282DNAJB6b-enriched small extracellular vesicles decrease polyglutamine aggregation in in vitro and in vivo models of Huntington diseaseBhagyashree S. Joshi0Sameh A. Youssef1Reinier Bron2Alain de Bruin3Harm H. Kampinga4Inge S. Zuhorn5Department of Biomedical Engineering, University of Groningen, University Medical Center Groningen, A. Deusinglaan 1, 9713 AV Groningen, the NetherlandsDepartment of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, the Netherlands; Department of Molecular Genetics, Department of Pediatrics, University Medical Center Groningen, Groningen, the NetherlandsDepartment of Biomedical Engineering, University of Groningen, University Medical Center Groningen, A. Deusinglaan 1, 9713 AV Groningen, the NetherlandsDepartment of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, the Netherlands; Department of Molecular Genetics, Department of Pediatrics, University Medical Center Groningen, Groningen, the NetherlandsDepartment of Biomedical Sciences of Cells and Systems, University of Groningen, University Medical Center Groningen, Groningen, the NetherlandsDepartment of Biomedical Engineering, University of Groningen, University Medical Center Groningen, A. Deusinglaan 1, 9713 AV Groningen, the Netherlands; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2589004221012517Cell biologyMolecular neuroscienceMolecular physiology |
| spellingShingle | Bhagyashree S. Joshi Sameh A. Youssef Reinier Bron Alain de Bruin Harm H. Kampinga Inge S. Zuhorn DNAJB6b-enriched small extracellular vesicles decrease polyglutamine aggregation in in vitro and in vivo models of Huntington disease iScience Cell biology Molecular neuroscience Molecular physiology |
| title | DNAJB6b-enriched small extracellular vesicles decrease polyglutamine aggregation in in vitro and in vivo models of Huntington disease |
| title_full | DNAJB6b-enriched small extracellular vesicles decrease polyglutamine aggregation in in vitro and in vivo models of Huntington disease |
| title_fullStr | DNAJB6b-enriched small extracellular vesicles decrease polyglutamine aggregation in in vitro and in vivo models of Huntington disease |
| title_full_unstemmed | DNAJB6b-enriched small extracellular vesicles decrease polyglutamine aggregation in in vitro and in vivo models of Huntington disease |
| title_short | DNAJB6b-enriched small extracellular vesicles decrease polyglutamine aggregation in in vitro and in vivo models of Huntington disease |
| title_sort | dnajb6b enriched small extracellular vesicles decrease polyglutamine aggregation in in vitro and in vivo models of huntington disease |
| topic | Cell biology Molecular neuroscience Molecular physiology |
| url | http://www.sciencedirect.com/science/article/pii/S2589004221012517 |
| work_keys_str_mv | AT bhagyashreesjoshi dnajb6benrichedsmallextracellularvesiclesdecreasepolyglutamineaggregationininvitroandinvivomodelsofhuntingtondisease AT samehayoussef dnajb6benrichedsmallextracellularvesiclesdecreasepolyglutamineaggregationininvitroandinvivomodelsofhuntingtondisease AT reinierbron dnajb6benrichedsmallextracellularvesiclesdecreasepolyglutamineaggregationininvitroandinvivomodelsofhuntingtondisease AT alaindebruin dnajb6benrichedsmallextracellularvesiclesdecreasepolyglutamineaggregationininvitroandinvivomodelsofhuntingtondisease AT harmhkampinga dnajb6benrichedsmallextracellularvesiclesdecreasepolyglutamineaggregationininvitroandinvivomodelsofhuntingtondisease AT ingeszuhorn dnajb6benrichedsmallextracellularvesiclesdecreasepolyglutamineaggregationininvitroandinvivomodelsofhuntingtondisease |