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Polyglutamin Diseases

開催日 2014/9/12
時間 9:00 - 10:00
会場 Room I(311+312)
Chairperson(s) 内山 安男 / Yasuo Uchiyama (順天堂大学医学研究科 神経疾患病態構造学講座 / Department of Cellular and Molecular Neuropathology Juntendo University Graduate School of Medicine, Japan)
永井 義隆 / Yoshitaka Nagai (独立行政法人国立精神・神経医療研究センター 神経研究所 疾病研究第四部 / Department of Degenerative Neurological Diseases, National Center of Neurology and Psychiatry, Japan)

A novel type of proteinopathy in brain neurons of NF-Y-deficient mice

  • O2-I-1-3
  • 山中 智行 / Tomoyuki Yamanaka:1,2,3,7 戸崎 麻子 / Asako Tosaki:2,7 黒澤 大 / Masaru Kurosawa:1,2,3,7 松本 弦 / Gen Matsumoto:1,2,3,7 小池 正人 / Masato Koike:4 内山 安男 / Yasuo Uchiyama:4 Maity Sankar N / Sankar N Maity:5 下郡 智美 / Tomomi Shimogori:3 服部 信孝 / Nobutaka Hattori:6 貫名 信行 / Nobuyuki Nukina:1,2,3,7 
  • 1:順大院・医・神経変性 / Neurode. Disord., Juntendo Univ. Med., Tokyo, Japan 2:理研・脳セ・構造神経病理 / Struc. Neuropa., RIKEN BSI, Saitama, Japan 3:理研・脳セ・視床発生 / Mol. Mech. Thalam. Dev., RIKEN BSI, Saitama, Japan 4:順大院・医・神経機能構造 / Cell Biol. Neurosc., Juntendo Univ. Med., Tokyo, Japan 5:テキサス大・MDACC、アメリカ / Med. Oncol., Univ. Texas MDACC, Texas, USA 6:順大院・医・脳神経内科 / Neurol., Juntendo Univ. Med., Tokyo, Japan 7:CREST JST / CREST JST, Tokyo, Japan 

Formation of inclusions containing misfolded and aggregated proteins is a typical pathological feature observed in many neurodegenerative diseases. NF-Y transcription factor regulates expression of chaperones involved in protein folding, and its sequestration and subsequent reduction of chaperone genes expression are shown in polyglutamine diseases including Huntington's disease. These observations lead us to hypothesize the potential significance of NF-Y in neuronal protein homeostasis. Here we show that neuronal inactivation of NF-Y in mouse brain neurons induces progressive neurodegeneration with distinctive ubiqutin/p62 pathology; they are not incorpotated into filamentous inclusion but co-accumulated with insoluble membrane proteins broadly on endoplasmic reticulum (ER). The degeneration also accompanies drastic increase in smooth ER without inducing ER stress. We further perform chromatin immunoprecipitation and identify several NF-Y physiological targets including an ER chaperone Grp94 potentially involved in ER disorganization. Thus, disruption of NF-Y-mediated gene transcription induces previously undescribed novel neuropathology accompanying ubiquitin/p62 accumulation on disorganized ER.

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