論文

査読有り
2006年8月

Huntingtin-associated protein 1 (HAP1) interacts with androgen receptor (AR) and suppresses SBMA-mutant-AR-induced apoptosis

HUMAN MOLECULAR GENETICS
  • Yukio Takeshita
  • ,
  • Ryutaro Fujinaga
  • ,
  • Changjiu Zhao
  • ,
  • Akie Yanai
  • ,
  • Koh Shinoda

15
15
開始ページ
2298
終了ページ
2312
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1093/hmg/ddl156
出版者・発行元
OXFORD UNIV PRESS

Huntingtin-associated protein 1 (HAP1), an interactor of huntingtin, has been known as an essential component of the stigmold 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 polyglutarnine 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-Iength-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.

Web of Science ® 被引用回数 : 31

リンク情報
DOI
https://doi.org/10.1093/hmg/ddl156
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/16782802
Web of Science
https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=JSTA_CEL&SrcApp=J_Gate_JST&DestLinkType=FullRecord&KeyUT=WOS:000239600500002&DestApp=WOS_CPL

エクスポート
BibTeX RIS