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Differential nuclear localization of complexes may underlie in vivo intrabody efficacy in Huntington's disease
Intrabodies offer attractive options for manipulating the protein misfolding that triggers neurodegenerative diseases. In Huntington's disease, where the expanded polyglutamine tract in the extreme N-terminal region of huntingtin exon1 misfolds, two lead intrabodies have been selected against a...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4191446/ https://www.ncbi.nlm.nih.gov/pubmed/25301961 http://dx.doi.org/10.1093/protein/gzu041 |
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author | Butler, D.C. Snyder-Keller, A. De Genst, E. Messer, A. |
author_facet | Butler, D.C. Snyder-Keller, A. De Genst, E. Messer, A. |
author_sort | Butler, D.C. |
collection | PubMed |
description | Intrabodies offer attractive options for manipulating the protein misfolding that triggers neurodegenerative diseases. In Huntington's disease, where the expanded polyglutamine tract in the extreme N-terminal region of huntingtin exon1 misfolds, two lead intrabodies have been selected against an adjacent peptide, using slightly different approaches. Both are effective at preventing aggregation of a reporter fragment in transient co-transfection assays. However, after intracranial delivery to mutant mouse brains, VL12.3, which is mainly localized to the nucleus, appears to accelerate the mutant phenotype, while C4 scFv, which is largely cytoplasmic, shows partial phenotypic correction. This comparison highlights parameters that could inform intrabody therapeutics for multiple proteostatic diseases. |
format | Online Article Text |
id | pubmed-4191446 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-41914462014-10-16 Differential nuclear localization of complexes may underlie in vivo intrabody efficacy in Huntington's disease Butler, D.C. Snyder-Keller, A. De Genst, E. Messer, A. Protein Eng Des Sel Creativity Engenders Next-Generation Antibody Engineering Intrabodies offer attractive options for manipulating the protein misfolding that triggers neurodegenerative diseases. In Huntington's disease, where the expanded polyglutamine tract in the extreme N-terminal region of huntingtin exon1 misfolds, two lead intrabodies have been selected against an adjacent peptide, using slightly different approaches. Both are effective at preventing aggregation of a reporter fragment in transient co-transfection assays. However, after intracranial delivery to mutant mouse brains, VL12.3, which is mainly localized to the nucleus, appears to accelerate the mutant phenotype, while C4 scFv, which is largely cytoplasmic, shows partial phenotypic correction. This comparison highlights parameters that could inform intrabody therapeutics for multiple proteostatic diseases. Oxford University Press 2014-10 /pmc/articles/PMC4191446/ /pubmed/25301961 http://dx.doi.org/10.1093/protein/gzu041 Text en © The Author 2014. Published by Oxford University Press. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Creativity Engenders Next-Generation Antibody Engineering Butler, D.C. Snyder-Keller, A. De Genst, E. Messer, A. Differential nuclear localization of complexes may underlie in vivo intrabody efficacy in Huntington's disease |
title | Differential nuclear localization of complexes may underlie in vivo intrabody efficacy in Huntington's disease |
title_full | Differential nuclear localization of complexes may underlie in vivo intrabody efficacy in Huntington's disease |
title_fullStr | Differential nuclear localization of complexes may underlie in vivo intrabody efficacy in Huntington's disease |
title_full_unstemmed | Differential nuclear localization of complexes may underlie in vivo intrabody efficacy in Huntington's disease |
title_short | Differential nuclear localization of complexes may underlie in vivo intrabody efficacy in Huntington's disease |
title_sort | differential nuclear localization of complexes may underlie in vivo intrabody efficacy in huntington's disease |
topic | Creativity Engenders Next-Generation Antibody Engineering |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4191446/ https://www.ncbi.nlm.nih.gov/pubmed/25301961 http://dx.doi.org/10.1093/protein/gzu041 |
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