title: Androgen-dependent neurodegeneration by polyglutamine-expanded human androgen receptor in Drosophila.
abstract: Spinal and bulbar muscular atrophy (SBMA) is an X-linked, adult-onset, neurodegenerative disorder affecting only males and is caused by expanded polyglutamine (polyQ) stretches in the N-terminal A/B domain of human androgen receptor (hAR). Although no overt phenotype was detected in adult fly eye photoreceptor neurons expressing mutant hAR (polyQ 52), ingestion of androgen or its known antagonists caused marked neurodegeneration with nuclear localization and structural alteration of the hAR mutant. Ligand-independent toxicity was detected with a truncated polyQ-expanded A/B domain alone, which was attenuated with cytosolic trapping by coexpression of the unliganded hAR E/F ligand binding domain. Thus, our findings suggest that the full binding of androgen to the polyQ-expanded hAR mutants leads to structural alteration with nuclear translocation that eventually results in the onset of SBMA in male patients.
authors.affiliation: Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, Japan.
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Takeyama
authors.forename: Saya
authors.initials: S
authors.lastname: Ito
authors.forename: Ayako
authors.initials: A
authors.lastname: Yamamoto
authors.forename: Hiromu
authors.initials: H
authors.lastname: Tanimoto
authors.forename: Takashi
authors.initials: T
authors.lastname: Furutani
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Kanuka
authors.forename: Masayuki
authors.initials: M
authors.lastname: Miura
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Tabata
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Kato
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified / Q000235:genetics; D001665:Binding Sites / Q000235:genetics; D019556:COS Cells; D004330:Drosophila / Q000235:genetics*; D018390:Gene Targeting; D006801:Humans; D009134:Muscular Atrophy, Spinal / Q000235:genetics / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism*; D017956:Photoreceptor Cells, Invertebrate / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D010455:Peptides; D011944:Receptors, Androgen; C097188:polyglutamine