| The accumulation of amyloids, formed by ss-sheet-rich proteins, into plaques in the brain, is associated with neurodegenerative disorders such as transmissible spongiform encephalopathies (TSEs), Alzheimer's, Parkinson's, and Huntington's diseases. Only TSEs are caused by self-propagating amyloid aggregates called prions. Yeast prions are infectious amyloids that cause distinct heritable phenotypic traits and often depend upon a glutamine (Q)/asparagine (N)-rich domain to assemble into ss-sheet-rich amyloid fibers. We showed that overexpression of many Q/N-rich proteins that can facilitate the de novo prion appearance also destabilizes pre-existing yeast prions. We demonstrated that this antagonistic effect of prion-like aggregates on heterologous prions is caused by the sequestration of cellular chaperones available to sever prions for proper propagation.;Yeast prions are not inherently toxic, although their co-presence with excess prion protein often produces an excess of soluble oligomers or amyloid aggregates that sequester essential cellular factors causing toxicity. We explored the mechanism of amyloid toxicity elicited by the interplay of heterologous Q/N-rich proteins and prions. We showed that the prion can drive the enhanced aggregation and phosphorylation of a heterologous Q/N-rich protein associated with toxicity. This toxicity is couple with impaired ubiquitin-proteasome system function, presumably due to proteasome capacity overload by hyperphosphorylated amyloid aggregates. |
