Stenoien D L, Cummings C J, Adams H P, Mancini M G, Patel K, DeMartino G N, Marcelli M, Weigel N L, Mancini M A
Department of Cell Biology, Baylor College of Medicine and VA Medical Center, One Baylor Plaza, Houston, TX 77030, USA.
Hum Mol Genet. 1999 May;8(5):731-41. doi: 10.1093/hmg/8.5.731.
Spinal bulbar muscular atrophy is a neurodegenerative disorder caused by a polyglutamine expansion in the androgen receptor (AR). We show in transiently transfected HeLa cells that an AR containing 48 glutamines (ARQ48) accumulates in a hormone-dependent manner in both cytoplasmic and nuclear aggregates. Electron microscopy reveals both types of aggregates to have a similar ultrastructure. ARQ48 aggregates sequester mitochondria and steroid receptor coactivator 1 and stain positively for NEDD8, Hsp70, Hsp90 and HDJ-2/HSDJ. Co-expression of HDJ-2/HSDJ significantly represses aggregate formation. ARQ48 aggregates also label with antibodies recognizing the PA700 proteasome caps but not 20S core particles. These results suggest that ARQ48 accumulates due to protein misfolding and a breakdown in proteolytic processing. Furthermore, the homeostatic disturbances associated with aggregate formation may affect normal cell function.
脊髓延髓性肌萎缩症是一种由雄激素受体（AR）中多聚谷氨酰胺扩增引起的神经退行性疾病。我们在瞬时转染的HeLa细胞中发现，含有48个谷氨酰胺的AR（ARQ48）以激素依赖的方式在细胞质和核聚集体中积累。电子显微镜显示这两种聚集体具有相似的超微结构。ARQ48聚集体隔离线粒体和类固醇受体辅激活因子1，并对NEDD8、Hsp70、Hsp90和HDJ-2/HSDJ呈阳性染色。HDJ-2/HSDJ的共表达显著抑制聚集体形成。ARQ48聚集体也能用识别PA700蛋白酶体帽但不能识别20S核心颗粒的抗体标记。这些结果表明，ARQ48由于蛋白质错误折叠和蛋白水解加工障碍而积累。此外，与聚集体形成相关的稳态紊乱可能会影响正常细胞功能。
