title: Wild type huntingtin toxicity in yeast: Implications for the role of amyloid cross-seeding in polyQ diseases.
abstract: Proteins with expanded polyglutamine (polyQ) regions are prone to form amyloids, which can cause diseases in humans and toxicity in yeast. Recently, we showed that in yeast non-toxic amyloids of Q-rich proteins can induce aggregation and toxicity of wild type huntingtin (Htt) with a short non-pathogenic polyglutamine tract. Similarly to mutant Htt with an elongated N-terminal polyQ sequence, toxicity of its wild type counterpart was mediated by induced aggregation of the essential Sup35 protein, which contains a Q-rich region. Notably, polymerization of Sup35 was not caused by the initial benign amyloids and, therefore, aggregates of wild type Htt acted as intermediaries in seeding Sup35 polymerization. This exemplifies a protein polymerization cascade which can generate a network of interdependent polymers. Here we discuss cross-seeded protein polymerization as a possible mechanism underlying known interrelations between different polyQ diseases. We hypothesize that similar mechanisms may enable proteins, which possess expanded Q-rich tracts but are not associated with diseases, to promote the development of polyQ diseases.
authors.affiliation: a Bach Institute of Biochemistry, Research Center of Biotechnology of the Russian Academy of Sciences , Moscow , Russia.
authors.forename: A I
authors.initials: AI
authors.lastname: Alexandrov
authors.affiliation: a Bach Institute of Biochemistry, Research Center of Biotechnology of the Russian Academy of Sciences , Moscow , Russia.
authors.forename: G V
authors.initials: GV
authors.lastname: Serpionov
authors.affiliation: a Bach Institute of Biochemistry, Research Center of Biotechnology of the Russian Academy of Sciences , Moscow , Russia.
authors.forename: V V
authors.initials: VV
authors.lastname: Kushnirov
authors.affiliation: a Bach Institute of Biochemistry, Research Center of Biotechnology of the Russian Academy of Sciences , Moscow , Russia.
authors.forename: M D
authors.initials: MD
authors.lastname: Ter-Avanesyan
mesh_terms: D000686:Amyloidosis / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000071058:Huntingtin Protein / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D010454:Peptide Termination Factors / Q000032:analysis / Q000378:metabolism; D010455:Peptides / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D066263:Protein Aggregation, Pathological / Q000235:genetics / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000032:analysis / Q000378:metabolism
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D010454:Peptide Termination Factors; D010455:Peptides; C068068:SUP35 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; C097188:polyglutamine
keywords: Amyloid; Huntington disease; Sup35; polyQ; polyglutamine; polymerization cross-seeding; yeast