Torashima Takashi, Koyama Chiho, Iizuka Akira, Mitsumura Kazuhiro, Takayama Kiyohiko, Yanagi Shigeru, Oue Miho, Yamaguchi Haruyasu, Hirai Hirokazu
Department of Neurophysiology, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan.
EMBO Rep. 2008 Apr;9(4):393-9. doi: 10.1038/embor.2008.31. Epub 2008 Mar 14.
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.
聚谷氨酰胺疾病是由扩展的聚谷氨酰胺蛋白（polyQ）积累引起的遗传性神经退行性疾病。此前，我们鉴定出一种新的鸟苷三磷酸酶CRAG，它在培养细胞中通过泛素-蛋白酶体途径促进聚Q聚集体的降解。由于CRAG在成人大脑中的表达降低，CRAG水平降低可能是聚谷氨酰胺疾病发病的基础。为了研究CRAG表达治疗聚谷氨酰胺疾病的潜力，我们构建了主要在浦肯野细胞中表达polyQ的模型小鼠。模型小鼠表现出浦肯野细胞树突分支不良、小脑明显萎缩和严重共济失调。慢病毒载体介导的CRAG在模型小鼠浦肯野细胞中的表达广泛清除了聚Q聚集体并重新激活了树突分化，从而显著缓解了共济失调。我们的体内数据证实了先前基于细胞培养的结果，并进一步扩展了靶向递送CRAG作为聚谷氨酰胺疾病基因治疗方法的实用性。
