Androgen-dependent neurodegeneration by polyglutamine-expanded human androgen receptor in Drosophila.
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.
Takeyama
Ken-ichi
K
Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, Japan.
Ito
Saya
S
Yamamoto
Ayako
A
Tanimoto
Hiromu
H
Furutani
Takashi
T
Kanuka
Hirotaka
H
Miura
Masayuki
M
Tabata
Tetsuya
T
Kato
Shigeaki
S
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*
D010455:Peptides; D011944:Receptors, Androgen; C097188:polyglutamine