Abstract
BackgroundPolyglutamine expansion is responsible for several neurodegenerative disorders, among which Huntington disease is the most well-known. Studies in the yeast model demonstrated that both aggregation and toxicity of a huntingtin (htt) protein with an expanded polyglutamine region strictly depend on the presence of the prion form of Rnq1 protein ([PIN +]), which has a glutamine/asparagine-rich domain.Principal FindingsHere, we showed that aggregation and toxicity of mutant htt depended on [PIN +] only quantitatively: the presence of [PIN +] elevated the toxicity and the levels of htt detergent-insoluble polymers. In cells lacking [PIN +], toxicity of mutant htt was due to the polymerization and inactivation of the essential glutamine/asparagine-rich Sup35 protein and related inactivation of another essential protein, Sup45, most probably via its sequestration into Sup35 aggregates. However, inhibition of growth of [PIN +] cells depended on Sup35/Sup45 depletion only partially, suggesting that there are other sources of mutant htt toxicity in yeast.ConclusionsThe obtained data suggest that induced polymerization of essential glutamine/asparagine-rich proteins and related sequestration of other proteins which interact with these polymers represent an essential source of htt toxicity.
Highlights
Expansion of polyglutamine stretches in nine otherwise unrelated human proteins causes neurodegenerative diseases accompanied by deposition of amyloid protein aggregates formed by these proteins
The obtained data suggest that induced polymerization of essential glutamine/asparagine-rich proteins and related sequestration of other proteins which interact with these polymers represent an essential source of htt toxicity
One of the most common polyQ disorders, Huntington disease, is caused by exon I IT15 mutations that increase the number of CAG triplets, coding for Q in the huntingtin protein and develops at a probability proportional to the number of these repeats
Summary
Expansion of polyglutamine (polyQ) stretches in nine otherwise unrelated human proteins causes neurodegenerative diseases accompanied by deposition of amyloid protein aggregates formed by these proteins. Expanded polyN stretches are similar to polyQ in their propensity to form aggregates in yeast and were used to model polyQ disorders since nuclear localization of such proteins causes transcriptional abnormalities and cell death [4]. Expressed htt with an expanded polyQ region was shown to be toxic, its toxicity and aggregation depended on the presence of [PIN+], the prion form of the QN-rich protein Rnq, known to facilitate the de novo appearance of other yeast prions [5,6]. Studies in the yeast model demonstrated that both aggregation and toxicity of a huntingtin (htt) protein with an expanded polyglutamine region strictly depend on the presence of the prion form of Rnq protein ([PIN+]), which has a glutamine/asparagine-rich domain
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