A specific nanobody prevents amyloidogenesis of D76N β2-microglobulin in vitro and modifies its tissue distribution in vivo.
Systemic amyloidosis is caused by misfolding and aggregation of globular proteins in vivo for which effective treatments are urgently needed. Inhibition of protein self-aggregation represents an attractive therapeutic strategy. Studies on the amyloidogenic variant of β2-microglobulin, D76N, causing...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Nature Publishing Group
2017
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| _version_ | 1797081858300706816 |
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| author | Raimondi, S Porcari, R Mangione, P Verona, G Marcoux, J Giorgetti, S Taylor, G Ellmerich, S Ballico, M Zanini, S Pardon, E Al-Shawi, R Simons, J Corazza, A Fogolari, F Leri, M Stefani, M Bucciantini, M Gillmore, J Hawkins, P Valli, M Stoppini, M Robinson, C Steyaert, J Esposito, G Bellotti, V |
| author_facet | Raimondi, S Porcari, R Mangione, P Verona, G Marcoux, J Giorgetti, S Taylor, G Ellmerich, S Ballico, M Zanini, S Pardon, E Al-Shawi, R Simons, J Corazza, A Fogolari, F Leri, M Stefani, M Bucciantini, M Gillmore, J Hawkins, P Valli, M Stoppini, M Robinson, C Steyaert, J Esposito, G Bellotti, V |
| author_sort | Raimondi, S |
| collection | OXFORD |
| description | Systemic amyloidosis is caused by misfolding and aggregation of globular proteins in vivo for which effective treatments are urgently needed. Inhibition of protein self-aggregation represents an attractive therapeutic strategy. Studies on the amyloidogenic variant of β2-microglobulin, D76N, causing hereditary systemic amyloidosis, have become particularly relevant since fibrils are formed in vitro in physiologically relevant conditions. Here we compare the potency of two previously described inhibitors of wild type β2-microglobulin fibrillogenesis, doxycycline and single domain antibodies (nanobodies). The β2-microglobulin -binding nanobody, Nb24, more potently inhibits D76N β2-microglobulin fibrillogenesis than doxycycline with complete abrogation of fibril formation. In β2-microglobulin knock out mice, the D76N β2-microglobulin/ Nb24 pre-formed complex, is cleared from the circulation at the same rate as the uncomplexed protein; however, the analysis of tissue distribution reveals that the interaction with the antibody reduces the concentration of the variant protein in the heart but does not modify the tissue distribution of wild type β2-microglobulin. These findings strongly support the potential therapeutic use of this antibody in the treatment of systemic amyloidosis. |
| first_indexed | 2024-03-07T01:19:59Z |
| format | Journal article |
| id | oxford-uuid:8ffe25cc-47c3-498d-90d7-3990cbe0df8c |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T01:19:59Z |
| publishDate | 2017 |
| publisher | Nature Publishing Group |
| record_format | dspace |
| spelling | oxford-uuid:8ffe25cc-47c3-498d-90d7-3990cbe0df8c2022-03-26T23:08:31ZA specific nanobody prevents amyloidogenesis of D76N β2-microglobulin in vitro and modifies its tissue distribution in vivo.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:8ffe25cc-47c3-498d-90d7-3990cbe0df8cEnglishSymplectic Elements at OxfordNature Publishing Group2017Raimondi, SPorcari, RMangione, PVerona, GMarcoux, JGiorgetti, STaylor, GEllmerich, SBallico, MZanini, SPardon, EAl-Shawi, RSimons, JCorazza, AFogolari, FLeri, MStefani, MBucciantini, MGillmore, JHawkins, PValli, MStoppini, MRobinson, CSteyaert, JEsposito, GBellotti, VSystemic amyloidosis is caused by misfolding and aggregation of globular proteins in vivo for which effective treatments are urgently needed. Inhibition of protein self-aggregation represents an attractive therapeutic strategy. Studies on the amyloidogenic variant of β2-microglobulin, D76N, causing hereditary systemic amyloidosis, have become particularly relevant since fibrils are formed in vitro in physiologically relevant conditions. Here we compare the potency of two previously described inhibitors of wild type β2-microglobulin fibrillogenesis, doxycycline and single domain antibodies (nanobodies). The β2-microglobulin -binding nanobody, Nb24, more potently inhibits D76N β2-microglobulin fibrillogenesis than doxycycline with complete abrogation of fibril formation. In β2-microglobulin knock out mice, the D76N β2-microglobulin/ Nb24 pre-formed complex, is cleared from the circulation at the same rate as the uncomplexed protein; however, the analysis of tissue distribution reveals that the interaction with the antibody reduces the concentration of the variant protein in the heart but does not modify the tissue distribution of wild type β2-microglobulin. These findings strongly support the potential therapeutic use of this antibody in the treatment of systemic amyloidosis. |
| spellingShingle | Raimondi, S Porcari, R Mangione, P Verona, G Marcoux, J Giorgetti, S Taylor, G Ellmerich, S Ballico, M Zanini, S Pardon, E Al-Shawi, R Simons, J Corazza, A Fogolari, F Leri, M Stefani, M Bucciantini, M Gillmore, J Hawkins, P Valli, M Stoppini, M Robinson, C Steyaert, J Esposito, G Bellotti, V A specific nanobody prevents amyloidogenesis of D76N β2-microglobulin in vitro and modifies its tissue distribution in vivo. |
| title | A specific nanobody prevents amyloidogenesis of D76N β2-microglobulin in vitro and modifies its tissue distribution in vivo. |
| title_full | A specific nanobody prevents amyloidogenesis of D76N β2-microglobulin in vitro and modifies its tissue distribution in vivo. |
| title_fullStr | A specific nanobody prevents amyloidogenesis of D76N β2-microglobulin in vitro and modifies its tissue distribution in vivo. |
| title_full_unstemmed | A specific nanobody prevents amyloidogenesis of D76N β2-microglobulin in vitro and modifies its tissue distribution in vivo. |
| title_short | A specific nanobody prevents amyloidogenesis of D76N β2-microglobulin in vitro and modifies its tissue distribution in vivo. |
| title_sort | specific nanobody prevents amyloidogenesis of d76n β2 microglobulin in vitro and modifies its tissue distribution in vivo |
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