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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...

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Autores principales: Butler, D.C., Snyder-Keller, A., De Genst, E., Messer, A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2014
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.
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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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