title: Amyloid-mediated sequestration of essential proteins contributes to mutant huntingtin toxicity in yeast.
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.
  
  
  RESULTS
  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.
authors.affiliation: A. N. Bach Institute of Biochemistry, Russian Academy of Sciences, Moscow, Russia.
authors.forename: Natalia V
authors.initials: NV
authors.lastname: Kochneva-Pervukhova
authors.forename: Alexander I
authors.initials: AI
authors.lastname: Alexandrov
authors.forename: Michael D
authors.initials: MD
authors.lastname: Ter-Avanesyan
mesh_terms: D000682:Amyloid / Q000494:pharmacology*; D002498:Centrifugation; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D050505:Mutant Proteins / Q000633:toxicity*; D009419:Nerve Tissue Proteins / Q000633:toxicity*; D010455:Peptides / Q000633:toxicity; D058105:Polymerization / Q000187:drug effects; D020836:Protein Structure, Quaternary; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*; D012967:Sodium Dodecyl Sulfate / Q000494:pharmacology; D012995:Solubility / Q000187:drug effects; D013997:Time Factors
chemical_list: D000682:Amyloid; D050505:Mutant Proteins; D009419:Nerve Tissue Proteins; D010455:Peptides; D011993:Recombinant Fusion Proteins; D029701:Saccharomyces cerevisiae Proteins; D049452:Green Fluorescent Proteins; C097188:polyglutamine; D012967:Sodium Dodecyl Sulfate