Mouse models of fragile X-associated tremor ataxia.
Mouse models of fragile X-associated tremor ataxia.
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DOI：
10.2310/jim.0b013e3181af59d6
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发表时间：
2009-12
期刊：
影响因子：
--
通讯作者：
Willemsen R
中科院分区：
文献类型：
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作者：
Berman RF;Willemsen R
描述脆性X相关颤动/共济失调(FXTAS)小鼠模型的建立及其行为、组织学和分子特征。本文对人类FXTAS的病理生理学和神经心理学特征与主要的FXTAS小鼠模型进行了比较。具体地说，描述了在Fmr1基因的5‘非翻译区携带扩展的CGG三核苷酸重复的转基因小鼠的发展，以及在这些小鼠中观察到的核内泛素阳性包涵体和行为Sequella的特征。CGG Ki小鼠模拟了FXTAS的许多重要特征，尽管有些方面在小鼠身上没有很好的模拟。FXTAS被很好地模拟的方面包括Fmr1mRNA水平升高，FMRP水平降低，随着年龄增长而发展的核内包涵体的存在，并在神经元中呈现类似的分布，以及神经心理和认知缺陷，包括运动功能低下，记忆受损和焦虑增加的证据。在这些小鼠中没有很好建模的FXTAS的特征包括在一些FXTAS患者中观察到的故意震颤，但在CGG Ki小鼠中尚未报告。此外，虽然FXTAS中星形胶质细胞中的核内包裹物非常明显，但在CGG Ki小鼠中观察到的相对较少。FXTAS的一些其他特征尚未在小鼠模型中进行系统检查，包括白质疾病、T2加权MRI高信号和脑萎缩，尽管我们的实验室目前正在对这些特征进行研究。可用的小鼠模型为FXTAS的分子生物学和病理生理学提供了有价值的见解，并将对未来开发和测试新的治疗方法特别有用。
To describe the development of mouse models of Fragile X-associated Tremor/Ataxia (FXTAS) and the behavioral, histological and molecular characteristics of these mice. This paper compares the pathophysiology and neuropsychological features of FXTAS in humans to the major mouse models of FXTAS. Specifically, the development of a transgenic mouse line carrying an expanded CGG trinucleotide repeat in the 5′untranslated regions of the Fmr1 gene is described along with a description of the characteristic intranuclear ubiquitin positive inclusions and the behavioral sequella observed in these mice. CGG KI mice model many of the important features of FXTAS, although some aspects are not well modeled in mice. Aspects of FXTAS that are modeled well include elevated levels of Fmr1 mRNA, reduced levels of Fmrp, the presence of intranuclear inclusions that develop with age and show similar distributions within neurons, and neuropsychological and cognitive deficits, including poor motor function, impaired memory and evidence of increased anxiety. Features of FXTAS that are not well modeled in these mice include intentional tremors that are observed in some FXTAS patients but have not been reported in CGG KI mice. In addition, while intranuclear inclusions in astrocytes are very prominent in FXTAS, there are relatively few observed in CGG KI mice. A number of additional features of FXTAS have not been systematically examined in mouse models yet, including white matter disease, hyperintensities in T2-weighted MRI, and brain atrophy, although these are currently under investigation in our laboratories. The available mouse model has provided valuable insights into the molecular biology and pathophysiology of FXTAS, and will be particularly useful for developing and testing new therapeutic treatments in the future.