Protofibril Binding Peptides Recognize and Inhibit Huntingtin Amyloid Formation <i>in vitro</i> and <i>in vivo</i>.

ABSTRACT: In Huntingtons disease, polyglutamine expansion in huntingtin exon 1 (Httex1) results in stepwise misfolding, amyloid formation, and neuronal death. Here we used mRNA display directed evolution to generate peptide ligands targeting Httex1 protofibrils, an early, toxic misfolding intermediate. Two distinct peptide families bind protofibrils, one tryptophan rich and the other glutamine rich, resulting in two predominant peptides HD1 (W-rich) and HD8 (Q-rich). Both peptides bind with high affinity and specificity to the misfolded polyQ structure present in protofibrils, a toxic component that is not recognized by existing huntingtin-directed antibodies. Homo- and heterodimers of HD1 and HD8 bind protofibrils with antibody-like affinity, and potently inhibit aggregation of recombinant and cell

SUBMITTER: Noridomi K 

PROVIDER: S-EPMC12633338 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature