title: Polyglutamine aggregates alter protein folding homeostasis in Caenorhabditis elegans.
abstract: Expansion of polyglutamine repeats in several unrelated proteins causes neurodegenerative diseases with distinct but related pathologies. To provide a model system for investigating common pathogenic features, we have examined the behavior of polyglutamine expansions expressed in Caenorhabditis elegans. The expression of polyglutamine repeats as green fluorescent protein (GFP)-fusion proteins in body wall muscle cells causes discrete cytoplasmic aggregates that appear early in embryogenesis and correlates with a delay in larval to adult development. The heat shock response is activated idiosyncratically in individual cells in a polyglutamine length-dependent fashion. The toxic effect of polyglutamine expression and the formation of aggregates can be reversed by coexpression of the yeast chaperone Hsp104. The altered homeostasis associated with polyglutamine aggregates causes both the sequestration of an otherwise soluble protein with shorter arrays of glutamine repeats and the relocalization of a nuclear glutamine-rich protein. These observations of induced aggregation and relocalization have implications for disorders involving protein aggregation.
authors.affiliation: Department of Biochemistry, Molecular Biology, and Cell Biology, Rice Institute for Biomedical Research, Northwestern University, Evanston, IL 60208, USA.
authors.forename: S H
authors.initials: SH
authors.lastname: Satyal
authors.forename: E
authors.initials: E
authors.lastname: Schmidt
authors.forename: K
authors.initials: K
authors.lastname: Kitagawa
authors.forename: N
authors.initials: N
authors.lastname: Sondheimer
authors.forename: S
authors.initials: S
authors.lastname: Lindquist
authors.forename: J M
authors.initials: JM
authors.lastname: Kramer
authors.forename: R I
authors.initials: RI
authors.lastname: Morimoto
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000254:growth & development / Q000378:metabolism*; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins; D006360:Heat-Shock Proteins / Q000235:genetics / Q000502:physiology; D015801:Helminth Proteins / Q000737:chemistry*; D006706:Homeostasis; D008164:Luminescent Proteins / Q000032:analysis / Q000235:genetics; D008856:Microscopy, Fluorescence; D018832:Molecular Chaperones / Q000235:genetics / Q000502:physiology; D010455:Peptides / Q000737:chemistry* / Q000235:genetics; D017510:Protein Folding; D011993:Recombinant Fusion Proteins / Q000737:chemistry; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000502:physiology; D029701:Saccharomyces cerevisiae Proteins; D013312:Stress, Physiological / Q000235:genetics / Q000378:metabolism; D018911:Trinucleotide Repeats
chemical_list: D006360:Heat-Shock Proteins; D015801:Helminth Proteins; D008164:Luminescent Proteins; D018832:Molecular Chaperones; D010455:Peptides; D011993:Recombinant Fusion Proteins; D029701:Saccharomyces cerevisiae Proteins; C070972:HsP104 protein, S cerevisiae; D049452:Green Fluorescent Proteins; C097188:polyglutamine