Gong Bing, Cao Zixuan, Zheng Ping, Vitolo Ottavio V, Liu Shumin, Staniszewski Agnieszka, Moolman Donna, Zhang Hong, Shelanski Michael, Arancio Ottavio
Department of Pathology and Taub Institute, Columbia University, New York, NY 10032, USA.
Cell. 2006 Aug 25;126(4):775-88. doi: 10.1016/j.cell.2006.06.046.
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 Abeta 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 IIalpha, PKA activity, and CREB phosphorylation.
神经元泛素/蛋白酶体途径与阿尔茨海默病（AD）的发病机制有关。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），是正常突触和认知功能所必需的。与HIV反式激活蛋白（TAT）的转导结构域融合的Uch-L1蛋白的转导，在经寡聚β淀粉样蛋白处理的海马切片以及AD的APP/PS1小鼠模型中，均可恢复正常的酶活性和突触功能。此外，随着时间的推移，腹腔注射融合蛋白可改善APP/PS1小鼠情境学习的保持能力。Uch-L1融合蛋白的有益作用与蛋白激酶A调节亚基IIα、蛋白激酶A活性和CREB磷酸化的正常水平的恢复有关。
