Extensive early motor and non-motor behavioral deficits are followed by striatal neuronal loss in knock-in Huntington's disease mice.
Extensive early motor and non-motor behavioral deficits are followed by striatal neuronal loss in knock-in Huntington's disease mice.
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DOI：
10.1016/j.neuroscience.2008.08.041
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发表时间：
2008-11-11
期刊：
影响因子：
3.3
通讯作者：
Chesselet MF
中科院分区：
文献类型：
--
作者：
Hickey MA;Kosmalska A;Enayati J;Cohen R;Zeitlin S;Levine MS;Chesselet MF
亨廷顿氏病是一种神经退行性疾病，由亨廷顿基因中CAG重复序列的延长引起。在小鼠亨廷顿蛋白基因中插入扩展的多聚谷氨酰胺重复序列的小鼠（敲入小鼠）最接近地模拟该疾病，因为突变在适当的基因组和蛋白质背景中表达。然而，很少有敲入小鼠品系已被广泛表征，现有数据表明其行为和病理表型的程度和时间过程存在显著差异。我们以前曾描述过行为异常，早在1个月大的开放领域，其次是在2个月的外观进行性亨廷顿神经病理学，在小鼠携带人类外显子1的一部分，约140 CAG重复插入到小鼠亨廷顿基因。在这里，我们扩展了这些观察结果，表明早期行为异常存在于广泛的运动（攀爬，垂直杆，旋转棒和转轮性能）和非运动功能（恐惧条件反射和焦虑）从1-4个月的年龄，并随后进行性胶质增生和DARPP 32减少（12个月）和纹状体神经元的损失在2年。在这个年龄，小鼠在其笼中也表现出显著的自发行为缺陷。数据显示，该基因敲入小鼠系再现了亨廷顿病的典型特征，之前有可能对应于人类疾病的延长的预显现阶段的缺陷。因此，他们提供了一个有用的模型，以阐明早期的病理生理机制和发展到明显的神经退行性变。
Huntington’s disease is a neurodegenerative disorder, caused by an elongation of CAG repeats in the huntingtin gene. Mice with an insertion of an expanded polyglutamine repeat in the mouse huntingtin gene (knock-in mice) most closely model the disease because the mutation is expressed in the proper genomic and protein context. However, few knock-in mouse lines have been extensively characterized and available data suggest marked differences in the extent and time course of their behavioral and pathological phenotype. We have previously described behavioral anomalies in the open field as early as 1 month of age, followed by the appearance at 2 months of progressive huntingtin neuropathology, in a mouse carrying a portion of human exon 1 with approximately 140 CAG repeats inserted into the mouse huntingtin gene. Here we extend these observations by showing that early behavioral anomalies exist in a wide range of motor (climbing, vertical pole, rotarod, and running wheel performance) and non-motor functions (fear conditioning and anxiety) starting at 1–4 months of age, and are followed by progressive gliosis and decrease in DARPP32 (12 months) and a loss of striatal neurons at 2 years. At this age, mice also present striking spontaneous behavioral deficits in their home cage. The data show that this line of knock-in mice reproduces canonical characteristics of Huntington’s disease, preceded by deficits which may correspond to the protracted pre-manifest phase of the disease in humans. Accordingly, they provide a useful model to elucidate early mechanisms of pathophysiology and the progression to overt neurodegeneration.
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影响因子：
4.1
作者：
Ghilardi, M. F.;Silvestri, G.;Eidelberg, D.
通讯作者：
Eidelberg, D.
影响因子：
2.9
作者：
Griffin, WC;Skinner, HD;Birkle, DL
通讯作者：
Birkle, DL
影响因子：
3.5
作者：
Bode, Felix J.;Stephan, Michael;von Hoersten, Stephan
通讯作者：
von Hoersten, Stephan
影响因子：
6.1
作者：
Hickey, MA;Gallant, K;Chesselet, MF
通讯作者：
Chesselet, MF
DOI：
10.1017/s1355617707070671
发表时间：
2007-05-01
影响因子：
2.6
作者：
Hinton, Sean C.;Paulsen, Jane S.;Rao, Stephen M.
通讯作者：
Rao, Stephen M.