Aggregation-prone proteins modulate huntingtin inclusion body formation in yeast.

Huntington's disease (HD) is a fatal neurodegenerative disorder caused by a polyglutamine expansion in the huntingtin (HTT) protein. The expression of mutant HTT in the baker's yeast Saccharomyces cerevisiae recapitulates many of the cellular phenotypes observed in mammalian HD models. Mutant HTT aggregation and toxicity in yeast is influenced by the presence of the Rnq1p and Sup35p prions, as well as other glutamine/asparagine-rich aggregation-prone proteins. Here we investigated the ability of a subset of these proteins to modulate mutant HTT aggregation and to substitute for the prion form of Rnq1p. We find that overexpression of either the putative prion Ybr016wp or the Sup35p prion restores aggregation of mutant HTT in yeast cells lacking the Rnq1p prion. These results indicate that an interchangeable suite of aggregation-prone proteins regulates mutant HTT aggregation dynamics in yeast, which may have implications for mutant HTT aggregation in human cells.