The proteasome-associated deubiquitinating enzyme Usp14 is essential for the maintenance of synaptic ubiquitin levels and the development of neuromuscular junctions.
The proteasome-associated deubiquitinating enzyme Usp14 is essential for the maintenance of synaptic ubiquitin levels and the development of neuromuscular junctions.
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DOI：
10.1523/jneurosci.2635-09.2009
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发表时间：
2009-09-02
期刊：
影响因子：
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通讯作者：
Wilson SM
中科院分区：
文献类型：
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作者：
Chen PC;Qin LN;Li XM;Walters BJ;Wilson JA;Mei L;Wilson SM
泛素蛋白酶体系统（UPS）的功能障碍与许多神经系统疾病的发病机制有关，包括阿尔茨海默病、脊髓小脑性共济失调和一些运动神经元疾病。最近的研究表明突触传递的改变可能在神经系统疾病的进展中起关键作用；然而，UPS调节突触结构和功能的机制尚未得到很好的表征。在本报告中，我们发现Usp14在神经肌肉连接（NMJs）的突触发育和功能中是不可或缺的。usp14缺失的axJ小鼠表现为静息震颤，肌肉质量减少，后肢明显僵硬，但没有任何可检测到的运动神经元损失。相反，Usp14的缺失会导致运动神经元终板的发育缺陷。突触前缺陷包括磷酸化的神经丝堆积、神经末梢发芽和运动神经末梢树突化不良，而突触后乙酰胆碱受体表现出不成熟的斑块样形态。NMJ的这些结构变化与脊髓和坐骨神经中泛素的丢失相关。进一步的研究表明，突触体部分的泛素损失最大，这表明终板肿胀可能是由突触蛋白质周转减少引起的。神经系统中Usp14的转基因修复纠正了运动神经元回路中单体泛素的水平以及在axJ小鼠的运动终板和肌肉中观察到的缺陷。这些数据确定了Usp14在哺乳动物突触中的关键作用，并表明蛋白酶体需要局部泛素循环来控制NMJs的发育和功能。
Dysfunction of the ubiquitin proteasome system (UPS) has been implicated in the pathogenesis of many neurological diseases, including Alzheimer's, spinocerebellar ataxia, and several motor neuron diseases. Recent research indicates that changes in synaptic transmission may play a critical role in the progression of neurological disease; however, the mechanisms by which the UPS regulates synaptic structure and function have not been well characterized. In this report, we show that Usp14 is indispensable for synaptic development and function at neuromuscular junctions (NMJs). Usp14-deficient axJ mice display a resting tremor, a reduction in muscle mass, and notable hind-limb rigidity without any detectable loss of motor neurons. Instead, loss of Usp14 causes developmental defects at motor neuron endplates. Presynaptic defects include phosphorylated neurofilament accumulations, nerve terminal sprouting and poor arborization of the motor nerve terminals, while postsynaptic acetylcholine receptors display immature plaque-like morphology. These structural changes in the NMJ correlated with ubiquitin loss in the spinal cord and sciatic nerve. Further studies demonstrated that the greatest loss of ubiquitin was found in synaptosomal fractions, suggesting that the endplate swellings may be caused by decreased protein turnover at the synapse. Transgenic restoration of Usp14 in the nervous system corrected the levels of monomeric ubiquitin in the motor neuron circuit and the defects that were observed in the motor endplates and muscles of the axJ mice. These data define a critical role for Usp14 at mammalian synapses and suggest a requirement for local ubiquitin recycling by the proteasome to control the development and function of NMJs.