Numerous diseases including Parkinson's disease, Alzheimer's disease, late-onset diabetes, and the transmissible spongiform encephalopathies are associated with the formation of amyloid fibrils. Despite considerable study, relatively little is known about the forces that drive amyloid fibril formation. Although amyloid-forming proteins share no obvious sequence homology, considerable evidence suggests that the fibrils share a common core structure.

The yeast prion [URE3] provides a powerful model system for studying amyloid fibril formation in vivo. [URE3] is the prion form of the yeast protein Ure2p; formation of [URE3] involves conversion of Ure2p into an infectious, amyloid form. We are using the [URE3] prion to dissect the sequence features that cause certain proteins to form amyloid fibrils. We found that when we randomized the order of the amino acids in the prion domain of Ure2p while keeping the overall amino acid composition unchanged, the resulting proteins retained their ability to form prions in vivo and amyloid fibrils in vitro. This suggests that amino acid composition, not primary sequence, drives amyloid fibril formation. We are now working to identify the sequence composition requirements for amyloid fibril formation and to determine whether these results can be extended to other amyloid forming proteins.

Additional interests include using yeast prions to examine the cellular response to amyloid, to identify potential therapeutic targets for the treatment of amyloid diseases and to examine why of all of the amyloid diseases, only a small subset are infectious.

Hansen JC, Lu X, Ross ED, Woody RW (2006) Intrinsic protein disorder, amino acid composition, and histone terminal domains. J Biol Chem. 281: 1853-1856.

Ross ED, Edskes HK, Terry MJ, Wickner RB (2005) Primary sequence independence for prion formation. Proc Natl Acad Sci USA. 102: 12825-12830.

Ross ED, Minton A, Wickner RB (2005) Prion domains: sequences, structures and interactions. Nat Cell Biol. 7: 1039-1044.

Ross ED, Baxa U, Wickner RB (2004) Scrambled prion domains form prions and amyloid. Mol Cell Biol. 24: 7206-13.

Ross ED, Wickner RB (2004) Prions of yeast fail to elicit a transcriptional response. Yeast 21: 963-72.

Wickner RB, Edskes HK, Ross ED, Pierce MM, Baxa U, Brachmann A, Shewmaker F (2004) Prion genetics: new rules for a new kind of gene. Annu Rev Genet. 38:681-707