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Differential nuclear localization of complexes may underlie in vivo intrabody efficacy in Huntington's disease.

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Butler, DC 
Snyder-Keller, A 
De Genst, E 
Messer, A 


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.



Huntington's disease, intrabody, nuclear, polyglutamine, single-chain Fv (scFv), Amino Acid Sequence, Animals, Cell Line, Cell Nucleus, Corpus Striatum, Cytoplasm, Female, Huntington Disease, Male, Mice, Molecular Sequence Data, Peptides, Protein Binding, Protein Folding, Rats, Recombinant Fusion Proteins, Single-Chain Antibodies, Transfection

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Protein Eng Des Sel

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Oxford University Press (OUP)
Biotechnology and Biological Sciences Research Council (BB/H003843/1)
Medical Research Council (G1002272)