Targeting Dyrk1A with AAVshRNA Attenuates Motor Alterations in TgDyrk1A, a Mouse Model of Down Syndrome
Targeting Dyrk1A with AAVshRNA Attenuates Motor Alterations in TgDyrk1A, a Mouse Model of Down Syndrome
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DOI：
10.1016/j.ajhg.2008.09.010
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发表时间：
2008-10-10
影响因子：
9.8
通讯作者：
Fillat, Cristina
中科院分区：
文献类型：
--
作者：
Ortiz-Abalia, Jon;Sahun, Ignasi;Fillat, Cristina
对唐氏综合症（DS）小鼠模型进行的遗传解剖研究指出，Dyrk] A过表达对唐氏综合症个体表现出的运动异常和认知缺陷起着关键作用。在本研究中，我们使用过表达Dyrk1A的小鼠模型（TgDyrk1A小鼠）来评估是否可以通过双侧腔内注射腺相关病毒2型（AAVshDyrk1A）传递针对dyrka的抑制RNA来纠正功能性中枢神经系统缺陷。我们报道了AAVshDyrk1A有效地转导HEK293细胞和原代神经元培养，触发对Dyrk1A表达的特异性抑制。将载体注射到TgDyrk1A小鼠的纹状体中导致纹状体的受限、长期转导。这种基因疗法被发现没有毒性，并成功地使TgDyrk1A小鼠的Dyrk1A蛋白水平正常化。重要的是，经过治疗的成年TgDyrk1A小鼠的行为研究显示，皮质皮质依赖性表型发生逆转，表现为过度活跃行为的减弱、运动协调缺陷的恢复以及感觉运动门控的改善。综上所述，这些数据表明，通过AAVshRNA使成年TgDyrk1A小鼠纹状体中的Dyrk1A基因表达正常化，可以明显逆转运动障碍。此外，这些结果确定Dyrk1A是治疗退行性痴呆的潜在靶点。
Genetic-dissection studies carried out with Down syndrome (DS) murine models point to the critical contribution of Dyrk] A overexpression to the motor abnormalities and cognitive deficits displayed in DS individuals. In the present study we have used a murine model overexpressing Dyrk1A (TgDyrk1A mice) to evaluate whether functional CNS defects could be corrected with an inhibitory RNA against Dyrk]A, delivered by bilateral intrastriatal injections of adeno-associated virus type 2 (AAVshDyrk1A). We report that AAVshDyrk1A efficiently transduced HEK293 cells and primary neuronal cultures, triggering the specific inhibition of Dyrk1A expression. Injecting the vector into the striata of TgDyrk1A mice resulted in a restricted, long-term transduction of the striatum. This gene therapy was found to be devoid of toxicity and succeeded in normalizing Dyrk1A protein levels in TgDyrk1A mice. Importantly, the behavioral studies of the adult TgDyrk1A mice treated showed a reversal of corticostriatal-dependent phenotypes, as revealed by the attenuation of their hyperactive behavior, the restoration of motor-coordination defects, and an improvement in sensorimotor gating. Taken together, the data demonstrate that normalizing Dyrk1A gene expression in the striatum of adult TgDyrk1A mice, by means of AAVshRNA, clearly reverses motor impairment. Furthermore, these results identify Dyrk1A as a potential target for therapy in DS.