• Top page
  • Timetable
  • Per session
  • Per presentation
  • How to
  • Meeting Planner



Depletion of p62/SQSTM1 reduces nuclear inclusions and paradoxically ameliorates disease phenotypes in Huntington's model mice

  • P3-305
  • 黒澤 大 / Masaru Kurosawa:1,3,7 松本 弦 / Gen Matsumoto:1,2,3 紀 嘉浩 / Yoshihiro Kino:1,2,3 奥野 弥佐子 / Misako Okuno:3 黒澤 みず樹 / Mizuki Kurosawa:3 谷口 晴美 / Harumi Taniguchi:1,2,3 中曽 一裕 / Kazuhiro Nakaso:4 柳川 透 / Toru Yanagawa:5 蕨 栄治 / Eiji Warabi:5 下郡 智美 / Tomomi Shimogori:1 櫻井 隆 / Takashi Sakurai:7 服部 信孝 / Hattori Nobutaka:6 貫名 信行 / Nobuyuki Nukina:1,2,3 
  • 1:理研・脳・視床発生 / Lab Molecular Mechanisms of Thalamus Development, RIKEN BSI, Saitama, Japan 2:順天堂大院・医・神経変性 / Dept Neuroscience for Neurodegenerative Disorders, Juntendo Univ Grad Sch of Med, Tokyo, Japan 3:理研・脳・構造神経病理 / Lab Structural Neuropathology, RIKEN BSI, Saitama, Japan 4:鳥取大・医・病態解析医学講座統合分子医化学分野 / Div of Medical Biochemistry, Tottori Univ Sch of Med, Tottori, Japan 5:筑波大・医 / Fac of Med, Univ of Tsukuba, Ibaraki, Japan 6:順天堂大院・医・神経学 / Dept Neurology, Juntendo Univ Grad Sch of Med, Tokyo, Japan 7:順天堂大院・医学研究科・細胞・分子薬理学 / Dept Cellular and Molecular Pharmacology, Juntendo Univ Grad Sch of Med, Tokyo, Japan 

Huntington's disease (HD) is a dominantly inherited genetic disease caused by mutant huntingtin (htt) protein with expanded polyglutamine (polyQ) tract. A neuropathological hallmark of HD is the presence of neuronal inclusions of mutant htt. p62 is an important regulatory protein in selective autophagy, a process by which aggregated proteins are degraded, and it is associated with several neurodegenerative disorders including HD. Here we investigated the effect of p62 depletion in two HD mouse models: R6/2 and HD190QG mice. We found that loss of p62 in both models led to longer lifespans and reduced nuclear inclusions, although cytoplasmic inclusions increased with polyQ length. In mouse embryonic fibroblasts (MEFs) with or without p62, mutant htt with a nuclear localization signal (NLS) showed no difference in nuclear inclusion between the two MEF types. In the case of mutant htt with a nuclear export signal (NES), however, p62 depletion increased cytoplasmic inclusions. Furthermore, to examine the effect of impaired autophagy in HD mouse models, we crossed R6/2 mice with Atg5 conditional knockout mice. These mice also showed decreased nuclear inclusions and increased cytoplasmic inclusions, similar to HD mice lacking p62. These data suggest that the genetic ablation of p62 in HD model mice enhances cytoplasmic inclusion formation by interrupting autophagic clearance of polyQ inclusions. This reduces polyQ nuclear influx and paradoxically ameliorates disease phenotypes by decreasing toxic nuclear inclusions.

Copyright © Neuroscience2014. All Right Reserved.