Ubiquitin hydrolase Uch-L1 rescues β-amyloid-induced decreases in synaptic function and contextual memory
Ubiquitin hydrolase Uch-L1 rescues β-amyloid-induced decreases in synaptic function and contextual memory
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DOI：
10.1016/j.cell.2006.06.046
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发表时间：
2006-08-25
期刊：
影响因子：
64.5
通讯作者：
Arancio, Ottavio
中科院分区：
文献类型：
--
作者：
Gong, Bing;Cao, Zixuan;Arancio, Ottavio
神经元泛素/蛋白酶体通路参与阿尔茨海默病（AD）的发病机制。我们现在表明，该途径的一个组成部分，泛素C-末端水解酶L1（Uch-L1），是正常的突触和认知功能所必需的。Uch-L1蛋白融合到HIV-反式激活蛋白（达特）的转导结构域的转导恢复正常的酶活性和突触功能，在海马切片与寡聚体A β和APP/PS1小鼠模型的AD。此外，随着时间的推移，腹膜内注射融合蛋白改善了APP/PS1小鼠的上下文学习的保留。Uch-L1融合蛋白的有益作用与PKA调节亚基II α、PKA活性和CREB磷酸化的正常水平的恢复有关。
The neuronal ubiquitin/proteasomal pathway has been implicated in the pathogenesis of Alzheimer's disease (AD). We now show that a component of the pathway, ubiquitin C-terminal hydrolase L1 (Uch-L1), is required for normal synaptic and cognitive function. Transduction of Uch-L1 protein fused to the transduction domain of HIV-transactivator protein (TAT) restores normal enzymatic activity and synaptic function both in hippocampal slices treated with oligomeric A beta and in the APP/PS1 mouse model of AD. Moreover, intraperitoneal injections with the fusion protein improve the retention of contextual learning in APP/PS1 mice over time. The beneficial effect of the Uch-L1 fusion protein is associated with restoration of normal levels of the PKA-regulatory subunit II alpha, PKA activity, and CREB phosphorylation.