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

D C Butler1, A Snyder-Keller1, E De Genst2

  • 1Wadsworth Center, New York State Department of Health, Department of Biomedical Sciences, University at Albany, Albany, NY 12208, USA.

Protein Engineering, Design & Selection : PEDS
|October 11, 2014
PubMed

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.

Keywords:
Huntington's diseaseintrabodynuclearpolyglutaminesingle-chain Fv (scFv)

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