title: Prefoldin protects neuronal cells from polyglutamine toxicity by preventing aggregation formation.
abstract: Huntington disease is caused by cell death after the expansion of polyglutamine (polyQ) tracts longer than ∼40 repeats encoded by exon 1 of the huntingtin (HTT) gene. Prefoldin is a molecular chaperone composed of six subunits, PFD1-6, and prevents misfolding of newly synthesized nascent polypeptides. In this study, we found that knockdown of PFD2 and PFD5 disrupted prefoldin formation in HTT-expressing cells, resulting in accumulation of aggregates of a pathogenic form of HTT and in induction of cell death. Dead cells, however, did not contain inclusions of HTT, and analysis by a fluorescence correlation spectroscopy indicated that knockdown of PFD2 and PFD5 also increased the size of soluble oligomers of pathogenic HTT in cells. In vitro single molecule observation demonstrated that prefoldin suppressed HTT aggregation at the small oligomer (dimer to tetramer) stage. These results indicate that prefoldin inhibits elongation of large oligomers of pathogenic Htt, thereby inhibiting subsequent inclusion formation, and suggest that soluble oligomers of polyQ-expanded HTT are more toxic than are inclusion to cells.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, USA.
authors.forename: Erika
authors.initials: E
authors.lastname: Tashiro
authors.forename: Tamotsu
authors.initials: T
authors.lastname: Zako
authors.forename: Hideki
authors.initials: H
authors.lastname: Muto
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Itoo
authors.forename: Karin
authors.initials: K
authors.lastname: Sörgjerd
authors.forename: Naofumi
authors.initials: N
authors.lastname: Terada
authors.forename: Akira
authors.initials: A
authors.lastname: Abe
authors.forename: Makoto
authors.initials: M
authors.lastname: Miyazawa
authors.forename: Akira
authors.initials: A
authors.lastname: Kitamura
authors.forename: Hirotake
authors.initials: H
authors.lastname: Kitaura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kubota
authors.forename: Mizuo
authors.initials: M
authors.lastname: Maeda
authors.forename: Takashi
authors.initials: T
authors.lastname: Momoi
authors.forename: Sanae M M
authors.initials: SM
authors.lastname: Iguchi-Ariga
authors.forename: Masataka
authors.initials: M
authors.lastname: Kinjo
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Ariga
mesh_terms: D016923:Cell Death; D045744:Cell Line, Tumor; D006801:Humans; D000071058:Huntingtin Protein; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D012995:Solubility
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D018832:Molecular Chaperones; D009419:Nerve Tissue Proteins; C115636:PFDN5 protein, human; D010455:Peptides; D012097:Repressor Proteins; C112806:prefoldin; C097188:polyglutamine
keywords: Cell Death; Chaperone Chaperonin; Neurodegeneration; Polyglutamine Disease; Protein Aggregation