Regulation of synaptic structure by ubiquitin C-terminal hydrolase L1.
Regulation of synaptic structure by ubiquitin C-terminal hydrolase L1.
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DOI：
10.1523/jneurosci.1817-09.2009
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发表时间：
2009-06-17
期刊：
影响因子：
--
通讯作者：
Patrick GN
中科院分区：
文献类型：
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作者：
Cartier AE;Djakovic SN;Salehi A;Wilson SM;Masliah E;Patrick GN
UCH-L1是一种去泛素化酶，在大脑中选择性地大量表达，其活性是正常突触功能所必需的。在这里，我们发现UCH-L1在维持海马神经元正常突触结构中起作用。我们发现，NMDA受体激活可使UCH-L1活性迅速上调，从而导致游离单体泛素水平的增加。相反，UCH-L1的药理抑制显著降低了单体泛素水平，并引起突触蛋白分布和脊柱形态的显著改变。抑制UCH-L1活性增加脊柱大小，同时降低脊柱密度。此外，突触前和突触后蛋白簇的大小也随之增加。然而，有趣的是，泛素的异位表达恢复了UCH-L1抑制神经元的正常突触结构。这些发现表明UCH-L1在突触重塑中的重要作用很可能是通过以活动依赖的方式调节游离单体泛素水平。
UCH-L1 is a de-ubiquitinating enzyme that is selectively and abundantly expressed in the brain, and its activity is required for normal synaptic function. Here, we show that UCH-L1 functions in maintaining normal synaptic structure in hippocampal neurons. We have found that UCH-L1 activity is rapidly up-regulated by NMDA receptor activation which leads to an increase in the levels of free monomeric ubiquitin. Conversely, pharmacological inhibition of UCH-L1 significantly reduces monomeric ubiquitin levels and causes dramatic alterations in synaptic protein distribution and spine morphology. Inhibition of UCH-L1 activity increases spine size while decreasing spine density. Furthermore, there is a concomitant increase in the size of pre and postsynaptic protein clusters. Interestingly, however, ectopic expression of ubiquitin restores normal synaptic structure in UCH-L1 inhibited neurons. These findings point to a significant role of UCH-L1 in synaptic remodeling most likely by modulating free monomeric ubiquitin levels in an activity-dependent manner.