Document Detail

Lentivector-mediated rescue from cerebellar ataxia in a mouse model of spinocerebellar ataxia.
MedLine Citation:
PMID:  18344973     Owner:  NLM     Status:  MEDLINE    
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.
Takashi Torashima; Chiho Koyama; Akira Iizuka; Kazuhiro Mitsumura; Kiyohiko Takayama; Shigeru Yanagi; Miho Oue; Haruyasu Yamaguchi; Hirokazu Hirai
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't     Date:  2008-03-14
Journal Detail:
Title:  EMBO reports     Volume:  9     ISSN:  1469-221X     ISO Abbreviation:  EMBO Rep.     Publication Date:  2008 Apr 
Date Detail:
Created Date:  2008-04-01     Completed Date:  2008-08-11     Revised Date:  2009-11-18    
Medline Journal Info:
Nlm Unique ID:  100963049     Medline TA:  EMBO Rep     Country:  England    
Other Details:
Languages:  eng     Pagination:  393-9     Citation Subset:  IM    
Department of Neurophysiology, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan.
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MeSH Terms
Dendrites / metabolism
GTP Phosphohydrolases / metabolism*,  therapeutic use
Gene Therapy / methods*
Genetic Vectors / genetics
Mice, Transgenic
Microscopy, Fluorescence
Peptides / metabolism*
Purkinje Cells / metabolism,  pathology*
Reverse Transcriptase Polymerase Chain Reaction
Spinocerebellar Ataxias / genetics,  metabolism,  therapy*
Reg. No./Substance:
0/Peptides; 26700-71-0/polyglutamine; EC 3.6.1.-/CRAG protein, mouse; EC 3.6.1.-/GTP Phosphohydrolases

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