Medical Genetics, University of Tuebingen, Tuebingen, Germany.
Neurobiol Dis. 2010 Feb;37(2):284-93. doi: 10.1016/j.nbd.2009.08.002. Epub 2009 Aug 20.
Spinocerebellar ataxia type 3 (SCA3), or Machado-Joseph disease (MJD), is caused by the expansion of a polyglutamine repeat in the ataxin-3 protein. We generated a mouse model of SCA3 expressing ataxin-3 with 148 CAG repeats under the control of the huntingtin promoter, resulting in ubiquitous expression throughout the whole brain. The model resembles many features of the disease in humans, including a late onset of symptoms and CAG repeat instability in transmission to offspring. We observed a biphasic progression of the disease, with hyperactivity during the first months and decline of motor coordination after about 1 year of age; however, intranuclear aggregates were not visible at this age. Few and small intranuclear aggregates appeared first at the age of 18 months, further supporting the claim that neuronal dysfunction precedes the formation of intranuclear aggregates.
脊髓小脑性共济失调 3 型（SCA3），又称 Machado-Joseph 病（MJD），是由ataxin-3 蛋白中的一个多谷氨酰胺重复扩展引起的。我们构建了一个 SCA3 的小鼠模型，该模型在亨廷顿蛋白启动子的控制下表达 148 个 CAG 重复的 ataxin-3，导致整个大脑中无处不在的表达。该模型类似于人类疾病的许多特征，包括症状的晚发和 CAG 重复在向后代传递中的不稳定性。我们观察到疾病的双相进展，在最初的几个月中表现为过度活跃，而在大约 1 岁后运动协调能力下降；然而，在这个年龄并没有看到核内聚集体。在 18 个月大时，首先出现少量和小的核内聚集体，这进一步支持了神经元功能障碍先于核内聚集体形成的说法。
