title: Differential nuclear localization of complexes may underlie in vivo intrabody efficacy in Huntington's disease.
abstract: 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.
authors.affiliation: Wadsworth Center, New York State Department of Health, Department of Biomedical Sciences, University at Albany, Albany, NY 12208, USA.
authors.forename: D C
authors.initials: DC
authors.lastname: Butler
authors.affiliation: Wadsworth Center, New York State Department of Health, Department of Biomedical Sciences, University at Albany, Albany, NY 12208, USA.
authors.forename: A
authors.initials: A
authors.lastname: Snyder-Keller
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
authors.forename: E
authors.initials: E
authors.lastname: De Genst
authors.affiliation: Wadsworth Center, New York State Department of Health, Department of Biomedical Sciences, University at Albany, Albany, NY 12208, USA Neural Stem Cell Institute, Rensselaer, NY 12144, USA annemesser@neuralsci.org.
authors.forename: A
authors.initials: A
authors.lastname: Messer
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000737:chemistry / Q000378:metabolism*; D003342:Corpus Striatum / Q000737:chemistry / Q000378:metabolism; D003593:Cytoplasm / Q000737:chemistry / Q000378:metabolism; D005260:Female; D006816:Huntington Disease / Q000378:metabolism*; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017510:Protein Folding; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D057127:Single-Chain Antibodies / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
chemical_list: D010455:Peptides; D011993:Recombinant Fusion Proteins; D057127:Single-Chain Antibodies; C097188:polyglutamine
keywords: Huntington's disease; intrabody; nuclear; polyglutamine; single-chain Fv (scFv)