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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Bibliographic Details
Published in:Protein engineering, design and selection design and selection, 2014-10, Vol.27 (10), p.359-363
Main Authors: Butler, D.C., Snyder-Keller, A., De Genst, E., Messer, A.
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Animals
Cell Line
Cell Nucleus - chemistry
Cell Nucleus - metabolism
Corpus Striatum - chemistry
Corpus Striatum - metabolism
Creativity Engenders Next-Generation Antibody Engineering
Cytoplasm - chemistry
Cytoplasm - metabolism
Female
Huntington Disease - metabolism
Male
Mice
Molecular Sequence Data
Peptides - chemistry
Peptides - genetics
Peptides - metabolism
Protein Binding
Protein Folding
Rats
Recombinant Fusion Proteins - chemistry
Recombinant Fusion Proteins - genetics
Recombinant Fusion Proteins - metabolism
Single-Chain Antibodies - chemistry
Single-Chain Antibodies - genetics
Single-Chain Antibodies - metabolism
Transfection
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Summary: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.
ISSN:1741-0126
1741-0134
DOI:10.1093/protein/gzu041