Lentivector-mediated rescue from cerebellar ataxia in a mouse model of spinocerebellar ataxia.
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.
Torashima
Takashi
T
Department of Neurophysiology, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan.
Koyama
Chiho
C
Iizuka
Akira
A
Mitsumura
Kazuhiro
K
Takayama
Kiyohiko
K
Yanagi
Shigeru
S
Oue
Miho
M
Yamaguchi
Haruyasu
H
Hirai
Hirokazu
H
D000818:Animals; D003712:Dendrites / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000378:metabolism* / Q000627:therapeutic use; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D007150:Immunohistochemistry; D016086:Lentivirus; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D010455:Peptides / Q000378:metabolism*; D011689:Purkinje Cells / Q000378:metabolism / Q000473:pathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020754:Spinocerebellar Ataxias / Q000235:genetics / Q000378:metabolism / Q000628:therapy*
D010455:Peptides; C097188:polyglutamine; C530558:CRAG protein, mouse; D020558:GTP Phosphohydrolases