Ubiquitin carboxyl-terminal hydrolase L1 is required for maintaining the structure and function of the neuromuscular junction
Ubiquitin carboxyl-terminal hydrolase L1 is required for maintaining the structure and function of the neuromuscular junction
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DOI：
10.1073/pnas.0911516107
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发表时间：
2010-01-26
影响因子：
11.1
通讯作者：
Lin, Weichun
中科院分区：
文献类型：
--
作者：
Chen, Fujun;Sugiura, Yoshie;Lin, Weichun
泛素羧基末端水解酶L1(UCH-L1)是哺乳动物神经系统中含量最丰富的蛋白质之一。在人类中，也在泛素化的包涵体中发现了UCH-L1，这些包涵体是大脑中神经退行性疾病的特征，表明它参与了神经退行性疾病。然而，UCH-L1在神经元中的生理作用仍有待进一步阐明。例如，以前的研究已经提供了支持和反对UCH-L1在大脑突触功能中作用的证据。在这里，我们描述了一种缺乏UCH-L1基因的基因敲除小鼠。我们发现，在缺乏UCH-L1的情况下，神经肌肉接头(NMJ)的突触传递明显受损。在UCH-L1基因敲除小鼠的NMJ处，自发和诱发的突触活动都减少；成对的脉冲促进受到损害，突触传递无法对高频重复刺激做出反应。对NMJ的形态分析进一步揭示了UCH-L1基因敲除小鼠的严重结构缺陷-突触前神经末梢突触小泡丢失和管泡状结构积累，以及肌肉失神经。这些发现表明，UCH-L1是维持NMJ结构和功能所必需的，正常UCH-L1活性的丧失可能导致周围神经系统的神经退化。
The enzyme ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) is one of the most abundant proteins in the mammalian nervous system. In humans, UCH-L1 is also found in the ubiquitinated inclusion bodies that characterize neurodegenerative diseases in the brain, suggesting its involvement in neurodegeneration. The physiologic role of UCH-L1 in neurons, however, remains to be further elucidated. For example, previous studies have provided evidence both for and against the role of UCH-L1 in synaptic function in the brain. Here, we have characterized a line of knockout mice deficient in the UCH-L1 gene. We found that, in the absence of UCH-L1, synaptic transmission at the neuromuscular junctions (NMJs) is markedly impaired. Both spontaneous and evoked synaptic activity are reduced; paired pulse-facilitation is impaired, and synaptic transmission fails to respond to high-frequency, repetitive stimulation at the NMJs of UCH-L1 knockout mice. Morphologic analyses of the NMJs further revealed profound structural defects-loss of synaptic vesicles and accumulation of tubulovesicular structures at the presynaptic nerve terminals, and denervation of the muscles in UCH-L1 knockout mice. These findings demonstrate that UCH-L1 is required for the maintenance of the structure and function of the NMJ and that the loss of normal UCH-L1 activity may result in neurodegeneration in the peripheral nervous system.