title: A protein polymerization cascade mediates toxicity of non-pathological human huntingtin in yeast.
abstract: Several neurodegenerative amyloidoses, including Huntington disease, are caused by expansion of polyglutamine (polyQ) stretches in otherwise unrelated proteins. In a yeast model, an N-terminal fragment of mutant huntingtin with a stretch of 103 glutamine residues aggregates and causes toxicity, while its non-toxic wild type variant with a sequence of 25 glutamines (Htt25Q) does not aggregate. Here, we observed that non-toxic polymers of various proteins with glutamine-rich domains could seed polymerization of Htt25Q, which caused toxicity by seeding polymerization of the glutamine/asparagine-rich Sup35 protein thus depleting the soluble pools of this protein and its interacting partner, Sup45. Importantly, only polymers of Htt25Q, but not of the initial benign polymers, induced Sup35 polymerization, indicating an intermediary role of Htt25Q in cross-seeding Sup35 polymerization. These data provide a novel insight into interactions between amyloidogenic proteins and suggest a possible role for these interactions in the pathogenesis of Huntington and other polyQ diseases.
authors.affiliation: Bach Institute of Biochemistry, Research Center of Biotechnology of the Russian Academy of Sciences. 33, bld. 2 Leninsky Ave., Moscow 119071, Russia.
authors.forename: Genrikh V
authors.initials: GV
authors.lastname: Serpionov
authors.affiliation: Bach Institute of Biochemistry, Research Center of Biotechnology of the Russian Academy of Sciences. 33, bld. 2 Leninsky Ave., Moscow 119071, Russia.
authors.forename: Alexander I
authors.initials: AI
authors.lastname: Alexandrov
authors.affiliation: Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Leninskie gori, 1, bldg. 40, Moscow 119991, Russia.
authors.forename: Yuri N
authors.initials: YN
authors.lastname: Antonenko
authors.affiliation: Bach Institute of Biochemistry, Research Center of Biotechnology of the Russian Academy of Sciences. 33, bld. 2 Leninsky Ave., Moscow 119071, Russia.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Ter-Avanesyan
mesh_terms: D000682:Amyloid / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000071058:Huntingtin Protein / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D006816:Huntington Disease / Q000235:genetics; D008856:Microscopy, Fluorescence; D010455:Peptides / Q000235:genetics; D058105:Polymerization; D000072002:Prion Proteins / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D055503:Protein Multimerization; D012441:Saccharomyces cerevisiae / Q000235:genetics* / Q000254:growth & development / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D013050:Spectrometry, Fluorescence; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*
chemical_list: D000682:Amyloid; C086055:HTT protein, human; D000071058:Huntingtin Protein; D010455:Peptides; D000072002:Prion Proteins; D029701:Saccharomyces cerevisiae Proteins; D049452:Green Fluorescent Proteins; C097188:polyglutamine