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ポリグルタミン病、ALS、脊髄小脳変性症、その他の神経変性疾患 2
Polyglutamine Diseases, ALS, SCD, Other Neurodegenerative Disorder 2

開催日 2014/9/11
時間 10:00 - 11:00
会場 Room I(311+312)
Chairperson(s) 柳 茂 / Shigeru Yanagi (東京薬科大学 生命科学部 分子性化学研究室 / Laboratory of Molecular Biochemistry, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Japan)
三澤 日出巳 / Hidemi Misawa (慶應義塾大学薬学部 薬理学 / Department of Pharmacology, Faculty of Pharmacy, Keio University, Japan)

異常伸長UGGAA リピートRNAはショウジョウバエにおいて神経毒性を引き起こす
Expanded UGGAA repeat RNA associated with SCA31 causes progressive neurodegeneration in Drosophila

  • O1-I-2-3
  • 石黒 太郎 / Taro Ishiguro:1,2 藤掛 伸宏 / Nobuhiro Fujikake:2 佐藤 望 / Nozomu Sato:1 和田 圭司 / Keiji Wada:2 水澤 英洋 / Hidehiro MIzusawa:1,3 永井 義隆 / Yoshitaka Nagai:2 石川 欽也 / Kinya Ishikawa:1 
  • 1:東京医科歯科大学 / Department of Neurology and Neurological science., Tokyo Medcal and Dental University, Japan 2:国立精神・神経セ神経研疾病4 / Dept. of Degenerative Neurolog. Dis., Natl. Inst. of Neuroscience, Natl. Ctr. of Neurol. and Psychiatry, Tokyo, Japan 3:国立精神・神経セ病院 / Natl. Ctr. of Neurol. and Psychiatry, Tokyo, Japan 

Increasing evidence indicates that RNA binding proteins and non-coding repeats RNA are associated with a number of neurodegeneration. We focus on Spinocerebellar ataxia type 31 (SCA31), which is a dominantly inherited neurodegenerative disease caused by insertion consisting of complex penta-nucleotide repeats containing long (TGGAA)n stretch in introns of TK2 (thymidine kinase 2) and BEAN (brain expressed, associated with Nedd4) (Am J Hum Genet, 2009; 85: 544-557). SCA31 could be considered one of the non-coding repeat disorders, because of its location of the mutation as well as the existence of the RNA foci in the human SCA31 Purkinje cell nuclei. We hypothesize that expanded UGGAA repeat RNA transcripts may lead to neurodegeneration. Here we generated transgenic flies expressing expanded UGGAA repeat and show that expanded UGGAA repeats indeed cause neurodegeneration. Expression of UGGAA repeats resulted in dramatic disruption of eye morphology in a dose-dependent manner and UGGAA RNA foci were observed in the nucleus and cytoplasm of eye imaginal disc in third instar larvae. Furthermore, we found that UGGAA repeat expression in neurons led to locomotor dysfunction and premature death, suggesting that expanded UGGAA repeats could cause neurodegeneration. Finally, we show the potent modifiers that could suppress UGGAA-induced toxicity in flies expressing expanded UGGAA. We therefore conclude that our new SCA31 model flies are useful to study the pathogenesis of SCA31, and possibly, other non-coding repeat RNA disorders.

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