Dominant prion mutants induce curing through pathways that promote chaperone-mediated disaggregation

Susanne Disalvo, Aaron Derdowski, John A. Pezza, Tricia R. Serio

Research output: Contribution to journalArticlepeer-review

35 Scopus citations


Protein misfolding underlies many neurodegenerative diseases, including the transmissible spongiform encephalopathies (prion diseases). Although cells typically recognize and process misfolded proteins, prion proteins evade protective measures by forming stable, self-replicating aggregates. However, coexpression of dominant-negative prion mutants can overcome aggregate accumulation and disease progression through currently unknown pathways. Here we determine the mechanisms by which two mutants of the Saccharomyces cerevisiae Sup35 protein cure the [PSI+] prion. We show that both mutants incorporate into wild-type aggregates and alter their physical properties in different ways, diminishing either their assembly rate or their thermodynamic stability. Whereas wild-type aggregates are recalcitrant to cellular intervention, mixed aggregates are disassembled by the molecular chaperone Hsp104. Thus, rather than simply blocking misfolding, dominant-negative prion mutants target multiple events in aggregate biogenesis to enhance their susceptibility to endogenous quality-control pathways.

Original languageEnglish (US)
Pages (from-to)486-493
Number of pages8
JournalNature Structural and Molecular Biology
Issue number4
StatePublished - Apr 2011

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology


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