Amyloid-mediated sequestration of essential proteins contributes to mutant huntingtin toxicity in yeast.

<h4>Background</h4>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 polyglutamin...

Descripción completa

Guardado en:
Detalles Bibliográficos
Autores principales: Natalia V Kochneva-Pervukhova, Alexander I Alexandrov, Michael D Ter-Avanesyan
Formato: article
Lenguaje:EN
Publicado: Public Library of Science (PLoS) 2012
Materias:
R
Q
Acceso en línea:https://doaj.org/article/a126f683c7864c849bda5424748fc5ef
Etiquetas: Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
Descripción
Sumario:<h4>Background</h4>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.<h4>Principal findings</h4>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.<h4>Conclusions</h4>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.