Onset and Progression of Behavioral and Molecular Phenotypes in a Novel Congenic R6/2 Line Exhibiting Intergenerational CAG Repeat Stability
Onset and Progression of Behavioral and Molecular Phenotypes in a Novel Congenic R6/2 Line Exhibiting Intergenerational CAG Repeat Stability
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DOI：
10.1371/journal.pone.0028409
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发表时间：
2011-12-07
期刊：
影响因子：
3.7
通讯作者：
Paylor, Richard
中科院分区：
文献类型：
--
作者：
Cowin, Randi-Michelle;Bui, Nghiem;Paylor, Richard
在本研究中，我们报告使用的速度同源产生一个C57 BL/6 J同源系的HD模型R6/2小鼠携带110 CAG重复，这独特地表现出最小的代际不稳定性。我们还报告了R6/2转基因插入位点的首次鉴定。110只CAG R6/2小鼠的相对稳定系的特征在于运动、认知和精神相关表型中的行为障碍的发作以及4至10周龄的疾病相关障碍的进展。110 Q小鼠表现出许多通常与R6/2模型相关的表型，包括活动减少和转棒性能受损。许多表型的发作发生在6周左右，并在年龄上进行性。此外，早在4周龄的小鼠中就观察到了一些表型。本研究还报告了新型R6/2小鼠中几种分子表型变化的发生和进展，以及这些变化与行为症状发生和进展的相关性。来自TR-FRET的数据表明突变蛋白状态变化（可溶性与聚集性）在疾病发作和进展中的关联。
In the present study we report on the use of speed congenics to generate a C57BL/6J congenic line of HD-model R6/2 mice carrying 110 CAG repeats, which uniquely exhibits minimal intergenerational instability. We also report the first identification of the R6/2 transgene insertion site. The relatively stable line of 110 CAG R6/2 mice was characterized for the onset of behavioral impairments in motor, cognitive and psychiatric-related phenotypes as well as the progression of disease-related impairments from 4 to 10 weeks of age. 110Q mice exhibited many of the phenotypes commonly associated with the R6/2 model including reduced activity and impairments in rotarod performance. The onset of many of the phenotypes occurred around 6 weeks and was progressive across age. In addition, some phenotypes were observed in mice as early as 4 weeks of age. The present study also reports the onset and progression of changes in several molecular phenotypes in the novel R6/2 mice and the association of these changes with behavioral symptom onset and progression. Data from TR-FRET suggest an association of mutant protein state changes (soluble versus aggregated) in disease onset and progression.