Epitope-specific antibodies can distinguish between soluble huntingtin exon-1 and its diverse cellular aggregates.

ABSTRACT: Misfolding and aggregation of huntingtin exon-1 (Httex1) with an expanded polyglutamine region is a key pathological hallmark of Huntington's disease, making conformationally specific Httex1 binders potentially valuable diagnostic or therapeutic tools. To define epitopes, which might confer conformationally specific Httex1 binding, we characterized five newly developed huntingtin antibodies (PHP5-PHP9). Binding to recombinant proteins as well as staining of human embryonic kidney 293 cells and R6/1 mice shows that PHP5 and PHP6 preferentially bind monomers over fibrils. Using electron paramagnetic resonance, peptide arrays, and deletion mutants, we mapped binding of PHP5 and PHP6 to the hydrophobic surface of an N-terminal α-helix spanning residues 4 to 18 of Httex1. In contrast, PHP7, PHP

SUBMITTER: Lugo J 

PROVIDER: S-EPMC12816906 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature