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EMBO reports 9, 4, 393–399 (2008)
doi:10.1038/embor.2008.31
AOP Published online: 14 March 2008
Lentivector-mediated rescue from cerebellar ataxia in a mouse model of spinocerebellar ataxia
Takashi Torashima1, 2, Chiho Koyama1, 3, Akira Iizuka1, Kazuhiro Mitsumura1, Kiyohiko Takayama1, Shigeru Yanagi4, Miho Oue1, 5, Haruyasu Yamaguchi5 & Hirokazu Hirai1, 2, 3
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1 Department of Neurophysiology, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan
2 Kanazawa University 21st Century COE Program, Kanazawa 920-8640, Japan
3 Solution Oriented Research for Science and Technology (SORST), Japan Science and Technology Agency, 4-1-8 Honcho Kawaguchi, Saitama 332-0012, Japan
4 Laboratory of Molecular Biochemistry, School of Life Science, Tokyo University of Pharmacy and Life Science, Hachioji, Tokyo 192-0392, Japan
5 Gunma University School of Health Sciences, 3-39-15 Showa-machi, Maebashi, Gunma 371-8514, Japan
To whom correspondence should be addressed
Hirokazu Hirai Tel: +81 27 220 7930; Fax: +81 27 220 7936; E-mail: hiraih@med.gunma-u.ac.jp
Received 29 May 2007; Accepted 6 February 2008; Published online 14 March 2008.
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Abstract
Polyglutamine disorders are inherited neurodegenerative diseases caused by the accumulation of expanded polyglutamine protein (polyQ). Previously, we identified a new guanosine triphosphatase, CRAG, which facilitates the degradation of polyQ aggregates through the ubiquitin–proteasome pathway in cultured cells. Because expression of CRAG decreases in the adult brain, a reduced level of CRAG could underlie the onset of polyglutamine diseases. To examine the potential of CRAG expression for treating polyglutamine diseases, we generated model mice expressing polyQ predominantly in Purkinje cells. The model mice showed poor dendritic arborization of Purkinje cells, a markedly atrophied cerebellum and severe ataxia. Lentivector-mediated expression of CRAG in Purkinje cells of model mice extensively cleared polyQ aggregates and re-activated dendritic differentiation, resulting in a striking rescue from ataxia. Our in vivo data substantiate previous cell-culture-based results and extend further the usefulness of targeted delivery of CRAG as a gene therapy for polyglutamine diseases.
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