Mice lacking caspase-2 are protected from behavioral changes, but not pathology, in the YAC128 model of Huntington disease.
Mice lacking caspase-2 are protected from behavioral changes, but not pathology, in the YAC128 model of Huntington disease.
复制标题
DOI：
10.1186/1750-1326-6-59
复制
发表时间：
2011-08-19
影响因子：
15.1
通讯作者：
Hayden MR
中科院分区：
文献类型：
--
作者：
Carroll JB;Southwell AL;Graham RK;Lerch JP;Ehrnhoefer DE;Cao LP;Zhang WN;Deng Y;Bissada N;Henkelman RM;Hayden MR
亨廷顿病（HD）是一种神经退行性疾病，其中半胱天冬酶激活和底物（包括亨廷顿蛋白）的切割被认为是一种病理机制。已表明胱天蛋白酶-2（Casp 2）活性的特定变化有助于HD的发病机制，然而独特的Casp 2切割底物仍然难以捉摸。因此，我们利用完全缺乏Casp 2（Casp 2-/-）的小鼠来检查Casp 2在HD进展中所起的作用。这种“底物不可知”的方法使我们能够在不预先定义感兴趣的蛋白水解底物的情况下查询Casp 2对HD进展的影响。缺乏Casp 2的YAC 128 HD模型小鼠显示出对HD的充分验证的运动和认知特征的保护，包括旋转棒、游泳T-迷宫、前脉冲抑制、自发交替和运动任务的表现。然而，YAC 128小鼠的特定病理学特征，包括纹状体体积损失和睾丸变性，在缺乏Casp 2的小鼠中没有改变。高分辨率磁共振成像（MRI）技术的应用验证了YAC 128小鼠中的特定神经病理学，该神经病理学不会因Casp 2的消融而改变。在没有病理学改善的情况下拯救行为表型表明，与导致细胞死亡和体积损失的过程相比，不同的途径可能在HD的神经回路功能障碍中起作用，导致行为变化。半胱天冬酶-2活性抑制可能与HD症状改善相关。
Huntington Disease (HD) is a neurodegenerative disorder in which caspase activation and cleavage of substrates, including the huntingtin protein, has been invoked as a pathological mechanism. Specific changes in caspase-2 (casp2) activity have been suggested to contribute to the pathogenesis of HD, however unique casp2 cleavage substrates have remained elusive. We thus utilized mice completely lacking casp2 (casp2-/-) to examine the role played by casp2 in the progression of HD. This 'substrate agnostic' approach allows us to query the effect of casp2 on HD progression without pre-defining proteolytic substrates of interest. YAC128 HD model mice lacking casp2 show protection from well-validated motor and cognitive features of HD, including performance on rotarod, swimming T-maze, pre-pulse inhibition, spontaneous alternation and locomotor tasks. However, the specific pathological features of the YAC128 mice including striatal volume loss and testicular degeneration are unaltered in mice lacking casp2. The application of high-resolution magnetic resonance imaging (MRI) techniques validates specific neuropathology in the YAC128 mice that is not altered by ablation of casp2. The rescue of behavioral phenotypes in the absence of pathological improvement suggests that different pathways may be operative in the dysfunction of neural circuitry in HD leading to behavioral changes compared to the processes leading to cell death and volume loss. Inhibition of caspase-2 activity may be associated with symptomatic improvement in HD.
登录
查看更多内容
影响因子：
4.8
作者：
Collins, DL;Holmes, CJ;Evans, AC
通讯作者：
Evans, AC
影响因子：
4.8
作者：
Gao, ZH;Shao, YF;Jiang, XJ
通讯作者：
Jiang, XJ
影响因子：
5.7
作者：
Lerch, Jason P.;Carroll, Jeffrey B.;Henkelman, R. Mark
通讯作者：
Henkelman, R. Mark
影响因子：
64.5
作者：
Graham, Rona K.;Deng, Yu;Hayden, Michael R.
通讯作者：
Hayden, Michael R.
影响因子：
4.8
作者：
LeBlanc, A;Liu, H;Hammond, J
通讯作者：
Hammond, J