Lentivector-mediated rescue from cerebellar ataxia in a mouse model of spinocerebellar ataxia
Lentivector-mediated rescue from cerebellar ataxia in a mouse model of spinocerebellar ataxia
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DOI：
10.1038/embor.2008.31
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发表时间：
2008-04-01
期刊：
影响因子：
7.7
通讯作者：
Hirai, Hirokazu
中科院分区：
文献类型：
--
作者：
Torashima, Takashi;Koyama, Chiho;Hirai, Hirokazu
多聚谷氨酰胺疾病是由扩展的多聚谷氨酰胺蛋白（polyQ）积累引起的遗传性神经退行性疾病。先前，我们鉴定了一种新的鸟苷三磷酸酶，CRAG，其通过在培养细胞中的泛素-蛋白酶体途径促进polyQ聚集体的降解。由于CRAG在成人脑中的表达减少，CRAG水平降低可能是多聚谷氨酰胺疾病发病的基础。为了检查CRAG表达用于治疗多聚谷氨酰胺疾病的潜力，我们产生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的树突状分支不良，小脑明显萎缩和严重共济失调。慢病毒载体介导的CRAG在模型小鼠的浦肯野细胞中的表达广泛地清除了polyQ聚集体并重新激活了树突状细胞分化，导致了对共济失调的显著拯救。我们的体内数据证实了以前的细胞培养为基础的结果，并进一步扩展了有用的CRAG作为多聚谷氨酰胺疾病的基因治疗靶向交付。
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.