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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)

CRAG enhances neuronal cell survival through SRF activation

  • O1-I-2-4
  • 柳 茂 / Shigeru Yanagi:1 福田 敏史 / Toshifumi Fukuda:1 稲留 涼子 / Ryoko Inatome:1 長島 駿 / Shun Nagashima:1 
  • 1:東京薬科大学 / Sch of Life Sci, Tokyo Univ of Pharm and Life Sci, Tokyo, Japan 

We previously demonstrated that CRMP5 (CRAM)-associated GTPase (CRAG), a short splicing variant of centaurin-γ3/AGAP3, facilitated degradation of misfolded proteins including expanded polyglutamine protein (polyQ) via the nuclear ubiquitin-proteasome pathway. Taking advantage of this feature, we previously showed that lentivirus-mediated CRAG expression in the Purkinje cells of mice expressing polyQ resulted in clearance of the polyQ aggregates and rescue from ataxia. Furthermore, we found that CRAG, but not centaurin-γ3, induces transcriptional activation of c-fos-dependent activator protein-1 (AP-1) via serum response factor (SRF). Thus, CRAG enhances the cell survival signal against the accumulation of misfolded proteins through not only proteasome activation, but also the activation of SRF-c-fos-mediated AP-1 activation in vitro. However, the function of CRAG in vivo remains unknown. Here we generated and analyzed CRAG-deficient mice. CRAG-deficient mice showed abnormal behavior and lethality within one mouth after birth due to neuronal dysfunction. Histological analysis indicated neuronal cell death and atrophy in CRAG-deficient mice. In this meeting, we discuss the mechanism underlying neuronal dysfunction caused by CRAG knockout. Our findings further extend the usefulness of targeted delivery of CRAG as a gene therapy for neurodegenerative diseases.

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