Department of Neurological Surgery, University of California, Davis; Davis, CA 95618, USA.
Brain Res. 2010 Mar 8;1318:155-66. doi: 10.1016/j.brainres.2009.12.077. Epub 2010 Jan 4.
Fragile X-associated tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disorder caused by CGG trinucleotide repeat expansions in the fragile X mental retardation 1 (FMR1) gene. The neuropathological hallmark of the disease is the presence of ubiquitin-positive intranuclear inclusions in neurons and in astrocytes. Ubiquitin-positive intranuclear inclusions have also been found in the neurons of transgenic mice model carrying an expanded CGG((98)) trinucleotide repeat of human origin but have not previously been described in glial cells. Therefore, we used immunocytochemical methods to determine the pathological features of nuclear and/or cytoplasmic inclusions in astrocytes, Bergmann glia, and neurons, as well as relationships between inclusion patterns, age, and repeat length in CGG knock-in (KI) mice in comparison with wild-type mice. In CGG KI mice, ubiquitin-positive intranuclear inclusions were found in neurons (e.g., pyramidal cells, GABAergic neurons) throughout the brain in cortical and subcortical brain regions; these inclusions increased in number and size with advanced age. Ubiquitin-positive intranuclear inclusions were also present in protoplasmic astrocytes, including Bergmann glia in the cerebellum. The morphology of intranuclear inclusions in CGG KI mice was compared to that of typical inclusions in human neurons and astrocytes in postmortem FXTAS brain tissue. This new finding of previously unreported pathology in astrocytes of CGG KI mice now provides an important mouse model to study astrocyte pathology in human FXTAS.
脆性 X 相关震颤/共济失调综合征（FXTAS）是一种成年发病的神经退行性疾病，由脆性 X 智力低下 1 基因（FMR1）中的 CGG 三核苷酸重复扩展引起。该疾病的神经病理学标志是神经元和星形胶质细胞中存在泛素阳性核内包涵体。在携带人类起源的扩展 CGG((98))三核苷酸重复的转基因小鼠模型中，也发现了泛素阳性核内包涵体，但以前未在神经胶质细胞中描述过。因此，我们使用免疫细胞化学方法来确定星形胶质细胞、Bergmann 胶质细胞和神经元中核内和/或细胞质包涵体的病理特征，以及在 CGG 敲入（KI）小鼠与野生型小鼠中，包涵体模式、年龄和重复长度之间的关系。在 CGG KI 小鼠中，泛素阳性核内包涵体存在于大脑皮质和皮质下脑区的神经元（例如，锥体神经元、GABA 能神经元）中；这些包涵体随着年龄的增长而数量和大小增加。在原浆星形胶质细胞中也存在泛素阳性核内包涵体，包括小脑的 Bergmann 胶质细胞。CGG KI 小鼠核内包涵体的形态与 FXTAS 人脑组织中典型神经元和星形胶质细胞中的包涵体进行了比较。这一在 CGG KI 小鼠星形胶质细胞中以前未报道过的病理学新发现，现在为研究人类 FXTAS 中星形胶质细胞病理学提供了一个重要的小鼠模型。
