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

Ralitsa B Kantcheva,Robert Mason,Flaviano Giorgini

doi:10.1371/currents.hd.501008f3051342c9a5c0cd0f3a5bf3a4

Ralitsa B Kantcheva, Robert Mason + Show 1 more

Open Access

https://doi.org/10.1371/currents.hd.501008f3051342c9a5c0cd0f3a5bf3a4

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Journal: PLOS Currents	Publication Date: Jan 1, 2014
Citations: 5	License type: cc-by

Affiliation: University of Leicester

Abstract

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.

Highlights

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease 1,2 caused by the expansion of a polyglutamine tract in the huntingtin (HTT) protein, which leads to its4,5 misfolding and aggregation[3 ]
As the presence of Rnq1p is crucial for the de novo formation of [PSI+] as well as the formation of mutant HTT aggregates in yeast, we investigated the connection between Sup35p expression and mutant HTT aggregation by overexpressing Sup35p
Our studies indicate that overexpression of Rnq1p, Sup35p and Ybr016wp can modulate the formation of mutant HTT aggregates in yeast

Summary

Introduction

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease 1,2 caused by the expansion of a polyglutamine (polyQ) tract in the huntingtin (HTT) protein, which leads to its4,5 misfolding and aggregation[3 ]. Several studies suggest that macromolecular HTT aggregates which prevent further intermolecular interactions are neuroprotective[8], while soluble oligomeric species of mutant HTT capable of sequestering other cellular proteins are neurotoxic[9 ]. A number of yeast models have been developed to study the cellular effects of mutant HTT expression. A number of yeast models have been developed to study the cellular effects of mutant HTT expression7,12,14 These models have shown that aggregation and cellular toxicity of mutant HTT in yeast is dependent upon the presence of the Rnq1p in its prion [PIN+] conformation[14 ], as deletion of RNQ1 or curing of [PIN+] ameliorates these phenotypes. The cellular function of Rnq1p is unclear, it is crucial for the de novo formation of [PSI+], the prion form of Sup35p16,17 . A recent study found that Sup35p interacts with mutant HTT through its Q/Nrich prion domain, and the presence of [PSI+] is critical for full toxicity of mutant HTT constructs with extended polyproline regions[19 ]

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