Takeshita Yukio, Fujinaga Ryutaro, Zhao Changjiu, Yanai Akie, Shinoda Koh
Department of Neuroscience, Yamaguchi University School of Medicine, Minami-Kogushi 1-1-1, Ube, Yamaguchi 755-8505, Japan.
Hum Mol Genet. 2006 Aug 1;15(15):2298-312. doi: 10.1093/hmg/ddl156. Epub 2006 Jun 16.
Huntingtin-associated protein 1 (HAP1), an interactor of huntingtin, has been known as an essential component of the stigmoid body (STB) and recently reported to play a protective role against neurodegeneration in Huntington's disease (HD). In the present study, subcellular association between HAP1 and androgen receptor (AR) with a long polyglutamine tract (polyQ) derived from spinal-and-bulbar-muscular-atrophy (SBMA) was examined using HEp-2 cells cotransfected with HAP1 and/or normal ARQ25, SBMA-mutant ARQ65 or deletion-mutant AR cDNAs. The results provided the first clear evidence that HAP1 interacts with AR through its ligand-binding domain in a polyQ-length-dependent manner and forms prominent inclusions sequestering polyQ-AR, and that addition of dihydrotestosterone reduces the association strength of HAP1 with ARQ25 more dramatically than that with ARQ65. Furthermore, SBMA-mutant-ARQ65-induced apoptosis was suppressed by cotransfection with HAP1. Our findings strongly suggest that HAP1/STB is relevant to polyQ-length-dependent modification on subcellular AR functions and critically involved in pathogenesis of not only HD but also SBMA as an important intrinsic neuroprotectant determining the threshold for cellular vulnerability to apoptosis. Taking together with previous reports that HAP1/STB is selectively expressed in the brain regions spared from degenerative targets in HD and SBMA, the current study might explain the region-specific occurrence of neurodegeneration in both diseases, shedding light on common aspects of their molecular pathological mechanism and yet-to-be-uncovered diagnostic or therapeutic applications for HD and SBMA patients.
亨廷顿蛋白相关蛋白1（HAP1）是亨廷顿蛋白的相互作用蛋白，已知是乙状结肠小体（STB）的重要组成部分，最近有报道称其在亨廷顿舞蹈病（HD）中对神经退行性变起保护作用。在本研究中，利用共转染了HAP1和/或正常ARQ25、脊髓延髓肌萎缩症（SBMA）突变型ARQ65或缺失突变型AR cDNA的HEp-2细胞，检测了HAP1与源自SBMA的具有长聚谷氨酰胺序列（polyQ）的雄激素受体（AR）之间的亚细胞关联。结果首次明确证明，HAP1通过其配体结合域以polyQ长度依赖的方式与AR相互作用，并形成隔离polyQ-AR的显著包涵体，且添加二氢睾酮对HAP1与ARQ25关联强度的降低作用比对ARQ65的作用更显著。此外，并转染HAP1可抑制SBMA突变型ARQ65诱导的细胞凋亡。我们的研究结果强烈表明，HAP1/STB与亚细胞AR功能上的polyQ长度依赖修饰相关，并且作为决定细胞对凋亡易感性阈值的重要内在神经保护剂，不仅在HD发病机制中起关键作用，在SBMA发病机制中也起关键作用。结合之前关于HAP1/STB在HD和SBMA中未发生退化的脑区选择性表达的报道，本研究可能解释了这两种疾病中神经退行性变的区域特异性发生情况，为它们分子病理机制的共同方面以及HD和SBMA患者尚未发现的诊断或治疗应用提供了线索。
