Androgen-dependent neurodegeneration by polyglutamine-expanded human androgen receptor in Drosophila
Androgen-dependent neurodegeneration by polyglutamine-expanded human androgen receptor in Drosophila
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DOI：
10.1016/s0896-6273(02)00875-9
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发表时间：
2002-08-29
期刊：
影响因子：
16.2
通讯作者：
Kato, S
中科院分区：
文献类型：
--
作者：
Takeyama, K;Ito, S;Kato, S
脊髓延髓肌萎缩症（SBMA）是一种X连锁的、成人发病的、仅影响男性的神经退行性疾病，由人雄激素受体（hAR）的N-末端A/B结构域中的扩展的多聚谷氨酰胺（polyQ）延伸引起。虽然没有明显的表型，在成年蝇眼感光神经元表达突变体hAR（polyQ 52），雄激素或其已知的拮抗剂的摄入引起显着的神经变性与核定位和结构改变的hAR突变体。单独用截短的polyQ-扩增的A/B结构域检测配体非依赖性毒性，其通过共表达未配体的hAR E/F配体结合结构域用胞质捕获减弱。因此，我们的研究结果表明，雄激素与polyQ扩增的hAR突变体的完全结合导致结构改变与核转位，最终导致男性患者中SBMA的发作。
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.