Reference: Kochneva-Pervukhova NV, et al. (2012) Amyloid-mediated sequestration of essential proteins contributes to mutant huntingtin toxicity in yeast. PLoS One 7(1):e29832

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Abstract

BACKGROUND: Polyglutamine 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 FINDINGS: Here, 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. CONCLUSIONS: 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.

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Journal Article
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Kochneva-Pervukhova NV, Alexandrov AI, Ter-Avanesyan MD
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