The folding, localization, and solubility of proteins are basic processes, essential for proper cellular function as well as organismal growth and development;yet the quality control mechanisms that ensure faithful execution of these events become increasingly compromised with age. Not surprisingly, when these normal pathways of protein biogenesis go awry there can be devastating consequences. For example, the age related protein misfolding diseases, including Alzheimer's, Parkinson's and Huntingdon's diseases, as well as a set of unique prion diseases termed the transmissible spongiform encephalopathy's [1, 2] are each associated with severe neurodegeneration resulting from the self-perpetuated misfolding of a normal, host encoded protein. In healthy individuals, these proteins are soluble and functional, but in afflicted individuals, the same protein misfolds and forms highly structured aggregates which appear to act as templates for the continued misfolding of normal protein, thereby promoting their own assembly. The budding yeast Saccharomyces cerevisiae expresses several prion proteins that also partition between soluble and aggregated forms in an analogous, self-templated process. In these cases, however, the prion form of these proteins is not associated with disease but instead acts as an epigenetic agent to direct the inheritance of a novel trait [3]. Given the experimental tractability of yeast and the viability of the prion state, this system provides an invaluable platform with which to dissect the mechanisms underlying self-replicating changes in protein conformations in vivo. Detailed information on the cis sequence requirements for efficient prion propagation has been gleaned from a number of in vivo studies on the yeast prion protein Sup35. Several mutations in the prion domain of this factor dominantly interfere with efficient prion propagation by the wildtype protein, suggesting that these variants specifically target crucial steps in the process. To gain insight into these events, I propose to elucidate the mechanisms by which these variants eliminate the misfolded form through a combination of in vivo and in vitro analyses. Together, these studies will define the key properties that endow a protein with self-replicating character and by extension highlight potential points of therapeutic intervention for the mammalian protein misfolding diseases.
| DiSalvo, Susanne; Serio, Tricia R (2011) Insights into prion biology: integrating a protein misfolding pathway with its cellular environment. Prion 5:76-83 |
| DiSalvo, Susanne; Derdowski, Aaron; Pezza, John A et al. (2011) Dominant prion mutants induce curing through pathways that promote chaperone-mediated disaggregation. Nat Struct Mol Biol 18:486-92 |
| Derdowski, Aaron; Sindi, Suzanne S; Klaips, Courtney L et al. (2010) A size threshold limits prion transmission and establishes phenotypic diversity. Science 330:680-3 |
