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 ph...

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Bibliographic Details
Published in:Neuron (Cambridge, Mass.) Mass.), 2002-08, Vol.35 (5), p.855-864
Main Authors: Takeyama, Ken-ichi, Ito, Saya, Yamamoto, Ayako, Tanimoto, Hiromu, Furutani, Takashi, Kanuka, Hirotaka, Miura, Masayuki, Tabata, Tetsuya, Kato, Shigeaki
Format: Article
Language:English
Subjects:
Animals
Animals, Genetically Modified - genetics
Binding Sites - genetics
COS Cells
Deoxyribonucleic acid
Disease
DNA
Drosophila - genetics
Gene Targeting
Genes
Humans
Insects
Ligands
Microscopy
Muscular Atrophy, Spinal - genetics
Muscular Atrophy, Spinal - metabolism
Neurodegeneration
Neurodegenerative Diseases - genetics
Neurodegenerative Diseases - metabolism
Peptides - metabolism
Photoreceptor Cells, Invertebrate - metabolism
Photoreceptors
Proteins
Receptors, Androgen - genetics
Receptors, Androgen - metabolism
Receptors, Androgen - physiology
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Summary: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.
ISSN:0896-6273
1097-4199
DOI:10.1016/S0896-6273(02)00875-9