title: Disruption of the toxic conformation of the expanded polyglutamine stretch leads to suppression of aggregate formation and cytotoxicity.
abstract: The polyglutamine (polyQ) diseases are a class of inherited neurodegenerative diseases including Huntington's disease, caused by the expansion of a polyQ stretch within each disease protein. This expansion is thought to cause a conformational change in the protein leading to aggregation of the protein, resulting in cytotoxicity. To analyze whether disrupting the toxic conformation of the polyQ protein can alter its aggregation propensity and cytotoxicity, we examined the effect of interruption of the expanded polyQ stretch by proline insertion, since prolines cause great alterations in protein conformation. Here, we show that insertion of prolines into the expanded polyQ stretch indeed disrupts its ordered secondary structure, leading to suppression of polyQ protein aggregation both in vitro and in cell culture, and reduction of cytotoxicity in correlation with the number of proline interruptions. Furthermore, we found that a short polyQ stretch with a proline interruption is able to inhibit aggregation of the expanded polyQ protein in trans. These results show that a gain in toxic conformation of the expanded polyQ protein is essential for aggregation and cytotoxicity, providing insight into establishing therapies against the polyQ diseases.
authors.affiliation: Division of Functional Genomics, Department of Post-Genomics and Diseases, Osaka University Graduate School of Medicine, 2-2-B9 Yamadaoka, Suita, Osaka, Japan.
authors.forename: Helena A
authors.initials: HA
authors.lastname: Popiel
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Nagai
authors.forename: Osamu
authors.initials: O
authors.lastname: Onodera
authors.forename: Takashi
authors.initials: T
authors.lastname: Inui
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Fujikake
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Urade
authors.forename: Warren J
authors.initials: WJ
authors.lastname: Strittmatter
authors.forename: James R
authors.initials: JR
authors.lastname: Burke
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ichikawa
authors.forename: Tatsushi
authors.initials: T
authors.lastname: Toda
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D019556:COS Cells; D002449:Cell Aggregation; D002942:Circular Dichroism; D004926:Escherichia coli / Q000378:metabolism; D009391:Nephelometry and Turbidimetry / Q000379:methods; D010455:Peptides / Q000737:chemistry* / Q000235:genetics / Q000633:toxicity*; D011392:Proline / Q000737:chemistry / Q000235:genetics; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000633:toxicity; D013056:Spectrophotometry, Ultraviolet
chemical_list: D010455:Peptides; D011994:Recombinant Proteins; C097188:polyglutamine; D011392:Proline