Abstract
Protein misfolding underlies many neurodegenerative diseases, including the Transmissible Spongiform Encephalopathies (prion diseases). While cells typically recognize and process misfolded proteins, prion proteins evade protective measures by forming stable, self-replicating aggregates. However, co-expression 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 wildtype aggregates and alter their physical properties in different ways, diminishing either their assembly rate or their thermodynamic stability. While wildtype 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.
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Published Version
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