Enhanced polyubiquitination of Shank3 and NMDA receptor in a mouse model of autism.
Enhanced polyubiquitination of Shank3 and NMDA receptor in a mouse model of autism.
复制标题
在自闭症的小鼠模型中，Shank3和NMDA受体的多泛素化增强。
DOI：
10.1016/j.cell.2011.03.052
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发表时间：
2011-05-27
期刊：
影响因子：
64.5
通讯作者：
Worley PF
中科院分区：
文献类型：
--
作者：
Bangash MA;Park JM;Melnikova T;Wang D;Jeon SK;Lee D;Syeda S;Kim J;Kouser M;Schwartz J;Cui Y;Zhao X;Speed HE;Kee SE;Tu JC;Hu JH;Petralia RS;Linden DJ;Powell CM;Savonenko A;Xiao B;Worley PF
我们已经创建了一个小鼠遗传模型，该模型模拟了人类Shank 3突变，该突变删除了C末端并与自闭症相关。Shank 3 ΔC蛋白表达为单拷贝[Shank 3（+/ΔC）小鼠]，与WT基因产物相互作用，导致突触处Shank 3减少> 90%。这种“功能获得”表型与WT Shank 3的多聚泛素化增加及其重新分布到蛋白酶体中有关。类似地，NMDA受体的NR 1亚基在突触处随着多聚泛素化的增加而减少。Shank 3（+/ΔC）小鼠的突触后密度蛋白、棘形态和突触数量的测定结果没有变化，但NMDAR反应的幅度降低，同时NMDAR依赖的LTP和LTD降低。Shank 3（+/ΔC）小鼠表现出行为缺陷，提示自闭症和NMDA受体功能降低。这些研究揭示了一种与单倍不足不同的机制，通过这种机制，Shank 3的突变可以引起自闭症样疾病。
We have created a mouse genetic model that mimics a human mutation of Shank3 that deletes the C-terminus and is associated with autism. Expressed as a single copy [Shank3(+/ΔC) mice], Shank3ΔC protein interacts with the WT gene product and results in >90 % reduction of Shank3 at synapses. This “gain of function” phenotype is linked to increased polyubiquitination of WT Shank3 and its redistribution into proteasomes. Similarly, the NR1 subunit of the NMDA receptor is reduced at synapses with increased polyubiquitination. Assays of post-synaptic density proteins, spine morphology and synapse number are unchanged in Shank3(+/ΔC) mice, but the amplitude of NMDAR responses is reduced together with reduced NMDAR-dependent LTP and LTD. Reciprocally, mGluR-dependent LTD is markedly enhanced. Shank3(+/ΔC) mice show behavioral deficits suggestive of autism and reduced NMDA receptor function. These studies reveal a mechanism distinct from haploinsufficiency by which mutations of Shank3 can evoke an autism-like disorder.
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DOI：
10.1097/chi.0b013e31818b1c63
发表时间：
2009-01
影响因子：
13.3
作者：
Rapoport J;Chavez A;Greenstein D;Addington A;Gogtay N
通讯作者：
Gogtay N
影响因子：
30.8
作者：
Durand, Christelle M.;Betancur, Catalina;Bourgeron, Thomas
通讯作者：
Bourgeron, Thomas
DOI：
10.1073/pnas.0906232107
发表时间：
2010-04-27
影响因子：
11.1
作者：
Gauthier, Julie;Champagne, Nathalie;Rouleau, Guy A.
通讯作者：
Rouleau, Guy A.
影响因子：
64.8
作者：
Brakeman, PR;Lanahan, AA;Worley, PF
通讯作者：
Worley, PF
影响因子：
16.2
作者：
Beneken, J;Tu, JC;Leahy, DJ
通讯作者：
Leahy, DJ