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

Nature Structural & Molecular Biology volume 18, pages 486–492 (2011)Cite this article

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Abstract

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.

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Figure 1: PNM mutants are distinguished by their effective inhibitory ratios.
Figure 2: PNM mutants incorporate into wild-type aggregates and alter multiple events in prion propagation.
Figure 3: PNM mutants alter the accumulation of propagons but not their transmission.
Figure 4: PNM expression promotes Hsp104-mediated disassembly of aggregates.

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Acknowledgements

We thank J. Bender, J. Laney, B. Cox, M. Tuite and members of the Serio, Laney and Tuite labs for helpful discussions and comments on the manuscript, and S. Lindquist (Whitehead Institute), D. Stillman (The University of Utah), M. Tuite (University of Kent), E. Craig (University of Wisconsin–Madison), J. Weissman (University of California, San Francisco) and J. Laney (Brown University) for reagents. We also thank C. Klaips and B. Rock for technical assistance. This research was supported by grants from the National Institutes of Health (AG032818 to S.D., GM085976 to A.D., GM080907 to J.A.P. and GM069802 to T.R.S.).

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  1. Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, Rhode Island, USA

    Susanne DiSalvo, Aaron Derdowski, John A Pezza & Tricia R Serio

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  1. Susanne DiSalvo
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S.D. and T.R.S. designed the experiments, analyzed the data and wrote the manuscript. S.D., A.D. and J.A.P. performed the experiments.

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Correspondence to Tricia R Serio.

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DiSalvo, S., Derdowski, A., Pezza, J. et al. Dominant prion mutants induce curing through pathways that promote chaperone-mediated disaggregation. Nat Struct Mol Biol 18, 486–492 (2011). https://doi.org/10.1038/nsmb.2031

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