Mouse models of the fragile X premutation and fragile X-associated tremor/ataxia syndrome.
Mouse models of the fragile X premutation and fragile X-associated tremor/ataxia syndrome.
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DOI：
10.1186/1866-1955-6-25
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发表时间：
2014
影响因子：
4.9
通讯作者：
Hukema RK
中科院分区：
文献类型：
--
作者：
Berman RF;Buijsen RA;Usdin K;Pintado E;Kooy F;Pretto D;Pessah IN;Nelson DL;Zalewski Z;Charlet-Bergeurand N;Willemsen R;Hukema RK
脆性X前突变（FPM）携带者在FMR 1的5′-UTR中具有55至200个CGG三核苷酸重复扩增，而一般人群的CGG重复长度在5至54之间。携带者曾经被认为没有症状，但现在认识到，他们可以发展各种早期神经系统症状，以及发展迟发性神经退行性疾病脆性X相关震颤/共济失调综合征（FXTAS）的风险。几种小鼠模型有助于我们对FPM和FXTAS的理解，使用这些模型的研究结果总结如下。这篇综述还讨论了这些信息如何提高我们对导致某些FPM携带者和FXTAS患者神经行为特征的分子和细胞异常的理解。小鼠模型显示了FPM携带者和FXTAS个体中观察到的许多病理学，包括Fmr 1 mRNA水平升高，脆性X智力低下蛋白水平降低和泛素阳性核内包涵体。几个脑区树突棘形态学异常与空间和时间记忆过程中的神经认知缺陷、运动表现受损和焦虑改变有关。体外研究已经确定了与异常Ca 2+动力学和电网络活动相关的树突和突触结构的改变。FPM小鼠在理解Fmr 1 mRNA、脆性X智力低下蛋白和潜在毒性聚甘氨酸肽在病理学中的翻译的作用方面特别有用。最后，考虑了使用这些和新兴小鼠模型进行治疗的临床前开发以改善FXTAS中的神经功能的潜力。
Carriers of the fragile X premutation (FPM) have CGG trinucleotide repeat expansions of between 55 and 200 in the 5′-UTR of FMR1, compared to a CGG repeat length of between 5 and 54 for the general population. Carriers were once thought to be without symptoms, but it is now recognized that they can develop a variety of early neurological symptoms as well as being at risk for developing the late onset neurodegenerative disorder fragile X-associated tremor/ataxia syndrome (FXTAS). Several mouse models have contributed to our understanding of FPM and FXTAS, and findings from studies using these models are summarized here. This review also discusses how this information is improving our understanding of the molecular and cellular abnormalities that contribute to neurobehavioral features seen in some FPM carriers and in patients with FXTAS. Mouse models show much of the pathology seen in FPM carriers and in individuals with FXTAS, including the presence of elevated levels of Fmr1 mRNA, decreased levels of fragile X mental retardation protein, and ubiquitin-positive intranuclear inclusions. Abnormalities in dendritic spine morphology in several brain regions are associated with neurocognitive deficits in spatial and temporal memory processes, impaired motor performance, and altered anxiety. In vitro studies have identified altered dendritic and synaptic architecture associated with abnormal Ca2+ dynamics and electrical network activity. FPM mice have been particularly useful in understanding the roles of Fmr1 mRNA, fragile X mental retardation protein, and translation of a potentially toxic polyglycine peptide in pathology. Finally, the potential for using these and emerging mouse models for preclinical development of therapies to improve neurological function in FXTAS is considered.
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DOI：
10.2310/jim.0b013e3181af59d6
发表时间：
2009-12
期刊：
Journal of investigative medicine : the official publication of the American Federation for Clinical Research
影响因子：
--
作者：
Berman RF;Willemsen R
通讯作者：
Willemsen R
DOI：
10.1002/ajmg.b.30910
发表时间：
2009-09-05
影响因子：
2.8
作者：
Brouwer, J. R.;Willemsen, R.;Oostra, B. A.
通讯作者：
Oostra, B. A.
DOI：
10.1073/pnas.0712197105
发表时间：
2008-02-19
影响因子：
11.1
作者：
Buxbaum, Joel N.;Ye, Zhengyi;Bartfai, Tamas
通讯作者：
Bartfai, Tamas
影响因子：
5.6
作者：
Berman RF;Murray KD;Arque G;Hunsaker MR;Wenzel HJ
通讯作者：
Wenzel HJ
影响因子：
3.5
作者：
Arocena, DG;Iwahashi, CK;Hagerman, PJ
通讯作者：
Hagerman, PJ