A variety of human neurodegenerative disorders are associated with expansions of polyglutamine (poly-Q) repeats in certain proteins 
. One well known example is Huntington's disease (HD), which is caused by an expansion of the poly-Q stretch, located within the N-terminal stretch of the essential protein called huntingtin (Htt) 
. Poly-Q expansion promotes formation of aggregates by the proteolytic Htt fragments containing an expanded poly-Q stretch 
. As the poly-Q-expanded N-terminal region of Htt is shown to aggregate and produce HD-like neurodegeneration in the mouse model, it is clear that this region is sufficient for reproducing the characteristic features of poly-Q aggregation and toxicity 
. Poly-Q associated pathologies can not be explained solely by the loss of the cellular function of a respective protein, e. g.
Htt (for review, see 
). Sequestration of other essential proteins by poly-Q aggregates was proposed to be a possible mechanism for toxicity 
. However, different experimental models suggested different candidates for sequestration 
, which decreased enthusiasm for the sequestration model.
To complicate matters further, expanded poly-Q proteins form various types of aggregates in mammalian cells 
. In the case of Htt, both nuclear and cytoplasmic aggregates were found 
. Their contributions to poly-Q pathogenicity remain a topic of intense discussion 
. At least, most researchers agree that one type of cytoplasmic aggregated structure, so-called “aggresome”, plays a cytoprotective role via assembling poly-Q expanded Htt at one site and possibly promoting its autophagy-dependent clearance 
. The aggresome is located perinuclearly, associated with the centrosome, and assembled with participation of the microtubular cytoskeleton. Other misfolded proteins can also be sequestered into an aggresome, indicating that this structure serves as a universal quality control depot for aggregating proteins 
Experimental assays for studying the molecular mechanism of poly-Q aggregation and toxicity have been developed in the yeast Saccharomyces cerevisiae
. It has been shown that cytoplasmic aggregation and toxicity of the chimeric protein, generated by a fusion of the expanded poly-Q stretch of Htt to the green fluorescent protein (GFP), is facilitated by the presence of the endogenous yeast prions, [PIN+
] and/or [PSI+
. In the absence of a prion, aggregates of this construct were rare, and no significant cytotoxicity was detected. However, in the presence of a prion, multiple peripherally located aggregates were formed, and cytotoxicity was observed 
. The prions [PIN+
] and [PSI+
] are self-perpetuating aggregates of the endogenous yeast proteins Rnq1 (unknown function) and Sup35 (translation termination, or release factor, also called eRF1), respectively (for review, see 
). Both of these proteins contain QN-rich prion domains (PrDs) that are responsible for aggregation properties (for review, see 
). It is likely that pre-existing prion aggregates nucleate aggregation of poly-Q expanded huntingtin. In the case of the Rnq1 prion, it was shown that poly-Q aggregates sequester some cytoskeletal components and inhibit endocytosis, which apparently contributes to cytotoxicity 
. Inhibition of endocytosis was also detected in mammalian cells expressing poly-Q 
. As mammalian Htt has been proposed to play a role in vesicle trafficking 
, these results are likely relevant to human HD.
Flanking sequences modulate poly-Q toxicity 
. In yeast strains containing the Rnq1 prion, cytotoxicity was eliminated by using a longer Htt fragment, which includes a proline (P)-rich stretch in addition to poly-Q. This P-rich stretch was shown to target aggregated poly-Q protein into a single perinuclear microtubule-dependent deposit, co-localized with the spindle body (yeast counterpart of a centrosome) and therefore resembling a mammalian aggresome 
. The cytoprotective role of the aggresome, as opposed to cytotoxicity of some other types of aggregates, recapitulates the situation previously observed in mammalian cells 
While the prion form of Sup35 protein ([PSI+
]) also promotes poly-Q toxicity in the yeast assay 
, the mechanism for this toxicity has not been studied in detail previously. In our current work, we demonstrate that [PSI+
]-dependent poly-Q toxicity is not counteracted by aggresome formation, but is ameliorated by an increased dosage of some components of the translational termination machinery. These data show that targets of poly-Q toxicity and the cytoprotective potential of the aggresome depend on the composition of endogenous aggregated proteins in a eukaryotic cell.