Disrupted GABAAR trafficking and synaptic inhibition in a mouse model of Huntington's disease.
Disrupted GABAAR trafficking and synaptic inhibition in a mouse model of Huntington's disease.
复制标题
DOI：
10.1016/j.nbd.2012.02.015
复制
发表时间：
2012-05
影响因子：
6.1
通讯作者：
Yan, Zhen
中科院分区：
文献类型：
--
作者：
Yuen, Eunice Y.;Wei, Jing;Zhong, Ping;Yan, Zhen
越来越多的证据表明，亨廷顿病(HD)是一种神经退行性运动障碍，由亨廷顿蛋白(HTT)和扩展的多聚谷氨酰胺(PolyQ)重复序列突变引起，与细胞内运输和突触功能改变有关。GABAA受体是突触抑制强度的关键决定因素，已被发现与亨廷顿蛋白相关蛋白1(HAP1)结合。HAP1作为连接GABAA受体和运动蛋白家族运动蛋白5(KIF5)的接头，控制GABAA受体沿树突内微管的运输。在这项研究中，我们发现在表达多Q-HTT的HD转基因小鼠模型中，GABAAR介导的突触传递显著受损，伴随着GABAA受体表面表达的减少。此外，在HD小鼠模型中，GABAAR/HAP1/KIF5复合体被破坏并从微管中解离。这些结果表明，HD患者GABAAR的转运和功能受损，可能是由于KIF5介导的基于微管的GABAA受体转运的干扰。抑制性突触效应的减弱可能导致兴奋性/抑制性平衡的丧失，导致HD神经元兴奋性毒性增加。
Growing evidence suggests that Huntington’s disease (HD), a neurodegenerative movement disorder caused by the mutant huntingtin (htt) with an expanded polyglutamine (polyQ) repeat, is associated with the altered intracellular trafficking and synaptic function. GABAA receptors, the key determinant of the strength of synaptic inhibition, have been found to bind to the huntingtin associated protein 1 (HAP1). HAP1 serves as an adaptor linking GABAA receptors to the kinesin family motor protein 5 (KIF5), controlling the transport of GABAA receptors along microtubules in dendrites. In this study, we found that GABAAR-mediated synaptic transmission is significantly impaired in a transgenic mouse model of HD expressing polyQ-htt, which is accompanied by the diminished surface expression of GABAA receptors. Moreover, the GABAAR/HAP1/KIF5 complex is disrupted and dissociated from microtubules in the HD mouse model. These results suggest that GABAAR trafficking and function is impaired in HD, presumably due to the interference of KIF5-mediated microtubule-based transport of GABAA receptors. The diminished inhibitory synaptic efficacy could contribute to the loss of the excitatory/inhibitory balance, leading to increased neuronal excitotoxicity in HD.
登录
查看更多内容
影响因子：
5.3
作者：
Li, SH;Gutekunst, CA;Li, XJ
通讯作者：
Li, XJ
影响因子：
64.8
作者：
LI, XJ;LI, SH;ROSS, CA
通讯作者：
ROSS, CA
影响因子：
5.3
作者：
Rong, Juan;McGuire, John R.;Li, Xiao-Jiang
通讯作者：
Li, Xiao-Jiang
影响因子：
3.5
作者：
Engelender, S;Sharp, AH;Ross, CA
通讯作者：
Ross, CA
影响因子：
16.2
作者：
Gu, XF;Li, CJ;Yang, XW
通讯作者：
Yang, XW