Formation of toxic oligomers of polyQ-expanded Huntingtin by prion-mediated cross-seeding

Michael H.M. Gropp, Courtney L. Klaips*, F. Ulrich Hartl

*Corresponding author for this work

    Research output: Contribution to journalArticleAcademicpeer-review

    7 Citations (Scopus)
    65 Downloads (Pure)

    Abstract

    Manifestation of aggregate pathology in Huntington's disease is thought to be facilitated by a preferential vulnerability of affected brain cells to age-dependent proteostatic decline. To understand how specific cellular backgrounds may facilitate pathologic aggregation, we utilized the yeast model in which polyQ-expanded Huntingtin forms aggregates only when the endogenous prion-forming protein Rnq1 is in its amyloid-like prion [PIN+] conformation. We employed optogenetic clustering of polyQ protein as an orthogonal method to induce polyQ aggregation in prion-free [pin] cells. Optogenetic aggregation circumvented the prion requirement for the formation of detergent-resistant polyQ inclusions but bypassed the formation of toxic polyQ oligomers, which accumulated specifically in [PIN+] cells. Reconstitution of aggregation in vitro suggested that these polyQ oligomers formed through direct templating on Rnq1 prions. These findings shed light on the mechanism of prion-mediated formation of oligomers, which may play a role in triggering polyQ pathology in the patient brain.

    Original languageEnglish
    Pages (from-to)4290-4306.e11
    Number of pages29
    JournalMolecular Cell
    Volume82
    Issue number22
    DOIs
    Publication statusPublished - 17-Nov-2022

    Keywords

    • cross-seeding
    • Huntington's disease
    • neurodegeneration
    • oligomers
    • optogenetics
    • polyQ
    • prion
    • protein aggregation
    • proteostasis
    • Rnq1

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