Comprehensive behavioral and molecular characterization of a new knock-in mouse model of Huntington's disease: zQ175.
Comprehensive behavioral and molecular characterization of a new knock-in mouse model of Huntington's disease: zQ175.
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DOI：
10.1371/journal.pone.0049838
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Howland D
中科院分区：
文献类型：
--
作者：
Menalled LB;Kudwa AE;Miller S;Fitzpatrick J;Watson-Johnson J;Keating N;Ruiz M;Mushlin R;Alosio W;McConnell K;Connor D;Murphy C;Oakeshott S;Kwan M;Beltran J;Ghavami A;Brunner D;Park LC;Ramboz S;Howland D
亨廷顿病（Huntington 'sdisease，HD）是一种以运动、认知和精神症状为特征的常染色体显性遗传神经退行性疾病。自1993年亨廷顿蛋白编码基因中CAG重复序列的不稳定扩增被鉴定为导致该疾病的突变以来，已经产生了许多HD小鼠模型来研究疾病发病机制并评估潜在的治疗方法。其中，基因敲入模型从遗传学角度最能模拟人类状况，因为它们在适当的遗传和蛋白质背景下表达突变。然而，在行为上，虽然在基因敲入小鼠模型中检测到一些异常表型，但需要具有比现有模型更早和更稳健的表型的模型。我们在这里首次描述了一种新的小鼠系，即zQ175基因敲入小鼠，它源自我们的CAG 140基因敲入群体中CAG拷贝数的自发扩增。鉴于通常在HD发病年龄和CAG重复序列长度之间观察到的反比关系，由于该新小鼠系携带显著更高的CAG重复序列长度，因此预期其比亲本系受损更显著。使用一系列行为测试，我们评估了杂合和纯合zQ175小鼠。纯合子小鼠表现出运动和握力异常，发病早（分别为8周龄和4周龄），随后在30周龄时出现转棒和攀爬活动缺陷，在1岁左右出现认知缺陷。对于翻译工作特别感兴趣的是，我们还发现杂合小鼠从大约4.5个月大开始就有明显的行为缺陷，特别是在昼夜循环的黑暗阶段。在杂合子和纯合子中均观察到体重下降，沿着纯合子中存活率显著降低。此外，我们检测到一个早期和显着减少的纹状体基因标记物从12周龄。这些数据表明，zQ175基因敲入细胞系可能是一个合适的模型，用于评价治疗方法和HD发病机制中的早期事件。
Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder characterized by motor, cognitive and psychiatric manifestations. Since the mutation responsible for the disease was identified as an unstable expansion of CAG repeats in the gene encoding the huntingtin protein in 1993, numerous mouse models of HD have been generated to study disease pathogenesis and evaluate potential therapeutic approaches. Of these, knock-in models best mimic the human condition from a genetic perspective since they express the mutation in the appropriate genetic and protein context. Behaviorally, however, while some abnormal phenotypes have been detected in knock-in mouse models, a model with an earlier and more robust phenotype than the existing models is required. We describe here for the first time a new mouse line, the zQ175 knock-in mouse, derived from a spontaneous expansion of the CAG copy number in our CAG 140 knock-in colony. Given the inverse relationship typically observed between age of HD onset and length of CAG repeat, since this new mouse line carries a significantly higher CAG repeat length it was expected to be more significantly impaired than the parent line. Using a battery of behavioral tests we evaluated both heterozygous and homozygous zQ175 mice. Homozygous mice showed motor and grip strength abnormalities with an early onset (8 and 4 weeks of age, respectively), which were followed by deficits in rotarod and climbing activity at 30 weeks of age and by cognitive deficits at around 1 year of age. Of particular interest for translational work, we also found clear behavioral deficits in heterozygous mice from around 4.5 months of age, especially in the dark phase of the diurnal cycle. Decreased body weight was observed in both heterozygotes and homozygotes, along with significantly reduced survival in the homozygotes. In addition, we detected an early and significant decrease of striatal gene markers from 12 weeks of age. These data suggest that the zQ175 knock-in line could be a suitable model for the evaluation of therapeutic approaches and early events in the pathogenesis of HD.
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影响因子：
3.3
作者：
Hickey MA;Kosmalska A;Enayati J;Cohen R;Zeitlin S;Levine MS;Chesselet MF
通讯作者：
Chesselet MF
DOI：
10.1602/neurorx.2.3.465
发表时间：
2005-07-01
期刊：
NeuroRx : the journal of the American Society for Experimental NeuroTherapeutics
影响因子：
--
作者：
Menalled, Liliana B
通讯作者：
Menalled, Liliana B
影响因子：
3.8
作者：
Brooks, SP;Betteridgea, H;Dunnett, SB
通讯作者：
Dunnett, SB
影响因子：
2.5
作者：
Menalled, LB;Sison, JD;Chesselet, MF
通讯作者：
Chesselet, MF
影响因子：
30.8
作者：
ANDREW, SE;GOLDBERG, YP;HAYDEN, MR
通讯作者：
HAYDEN, MR