A protein polymerization cascade mediates toxicity of non-pathological human huntingtin in yeast.

Genrikh V Serpionov,Michael D Ter-Avanesyan,Yuri N Antonenko,Alexander I Alexandrov

doi:10.1038/srep18407

Abstract

Several neurodegenerative amyloidoses, including Huntington disease, are caused by expansion of polyglutamine (polyQ) stretches in otherwise unrelated proteins. In a yeast model, an N-terminal fragment of mutant huntingtin with a stretch of 103 glutamine residues aggregates and causes toxicity, while its non-toxic wild type variant with a sequence of 25 glutamines (Htt25Q) does not aggregate. Here, we observed that non-toxic polymers of various proteins with glutamine-rich domains could seed polymerization of Htt25Q, which caused toxicity by seeding polymerization of the glutamine/asparagine-rich Sup35 protein thus depleting the soluble pools of this protein and its interacting partner, Sup45. Importantly, only polymers of Htt25Q, but not of the initial benign polymers, induced Sup35 polymerization, indicating an intermediary role of Htt25Q in cross-seeding Sup35 polymerization. These data provide a novel insight into interactions between amyloidogenic proteins and suggest a possible role for these interactions in the pathogenesis of Huntington and other polyQ diseases.

Highlights

Previously revealed that aggregation of mutant Htt results in defects of various processes, such as endocytosis, tryptophan metabolism, translation, cell cycle progression and endoplasmic reticulum-associated protein degradation[15,19,20,21,22]
We observed that polymers of artificial proteins with long polyQ or polyQ interspersed with other residues, which are not toxic on their own[28], seeded polymerization of wild type Htt, which resulted in cytotoxicity
Since proteins with long polyQ form aggregates that sequester proteins with short polyQ, which cannot aggregate on their own[32,33,34,35,36], one can suggest that polymers of proteins with long polyQ stretches act as efficient seeds for Htt25Q-green fluorescent protein (GFP) polymerization

Summary

Introduction

Previously revealed that aggregation of mutant Htt results in defects of various processes, such as endocytosis, tryptophan metabolism, translation, cell cycle progression and endoplasmic reticulum-associated protein degradation[15,19,20,21,22]. In yeast toxicity of mutant Htt is usually studied when this protein is expressed alone, in humans the pathologic effects of the mutant HTT allele are manifested in the presence of its wild type counterpart, and some results indicate a role of non-pathological Htt in disease progression[25]. This role, can be complex, i.e. for Htt with shorter pathological polyQ, increasing the length of the polyQ in wild type Htt seems to exacerbate disease severity, while for mutant Htt with longer polyQ length, the effect is opposite[26]. The obtained results may be relevant for elucidation of the pathogenesis of Huntington and other polyQ diseases as well as for understanding of importance of the phenomenon of amyloid interdependence

Methods

Results

Conclusion