Normal Molecular Specification and Neurodegenerative Disease-Like Death of Spinal Neurons Lacking the SNARE-Associated Synaptic Protein Munc18-1
Normal Molecular Specification and Neurodegenerative Disease-Like Death of Spinal Neurons Lacking the SNARE-Associated Synaptic Protein Munc18-1
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DOI：
10.1523/jneurosci.1964-15.2016
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发表时间：
2016-01-13
影响因子：
5.3
通讯作者：
Kania, Artur
中科院分区：
文献类型：
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作者：
Law, Chris;Profes, Marcos Schaan;Kania, Artur
突触活动在神经回路早期形成过程中的作用是一个有争议的话题;通过删除Munc 18 -1基因来基因消融神经递质释放提供了一个很好的模型来回答早期回路形成是否需要这种活动的问题。先前对Muncl 8 -1（-/-）小鼠突变体的分析记录了它们大体上正常的神经系统，但尚未评估其分子分化。小鼠中Munc 18 -1缺失也导致广泛的神经变性，其特征仍然很差。在这项研究中，我们证明了脊髓运动回路形成的早期阶段，包括运动神经元的规格，轴突生长和寻路，和mRNA表达，在1VIunc 18 -1（-/-）小鼠中不受影响，表明突触活动是早期神经系统发育所必需的。此外，我们发现Munc 18 -1缺失引起的神经变性是细胞自主的，与几种神经营养因子的明显正常表达和正常GDNF信号传导一致。与细胞自主变性一致，我们证明了Munc 18 -1（-/-）神经元中突触蛋白Syntaxinla和PSD-95以及TrkB和DCC受体的运输缺陷;这些缺陷似乎不会引起ER应激，这表明了变性的其他机制。最后，我们证明了阿尔茨海默病的病理相似性，如改变Tau磷酸化，神经元缠结和不溶性蛋白质斑块的积累。总之，我们的研究结果揭示了在Munc 18 -1（-/-）小鼠中观察到的神经变性，并认为这种现象与神经变性疾病有相似之处。
The role of synaptic activity during early formation of neural circuits is a topic of some debate; genetic ablation of neurotransmitter release by deletion of the Munc18-1 gene provides an excellent model to answer the question of whether such activity is required for early circuit formation. Previous analysis of Muncl8-1(-/-) mouse mutants documented their grossly normal nervous system, but its molecular differentiation has not been assessed. Munc18-1 deletion in mice also results in widespread neurodegeneration that remains poorly characterized. In this study, we demonstrate that the early stages of spinal motor circuit formation, including motor neuron specification, axon growth and pathfinding, and mRNA expression, are unaffected in 1VIunc18-1(-/-) mice, demonstrating that synaptic activity is dispensable for early nervous system development. Furthermore, we show that the neurodegenerat ion caused by Munc18-1 loss is cell autonomous, consistent with apparently normal expression of several neurotrophic factors and normal GDNF signaling. Consistent with cell-autonomous degeneration, we demonstrate defects in the trafficking of the synaptic proteins Syntaxinla and PSD-95 and the TrkB and DCC receptors in Munc18-1(-/-) neurons; these defects do not appear to cause ER stress, suggesting other mechanisms for degeneration. Finally, we demonstrate pathological similarities to Alzheimer's disease, such as altered Tau phosphorylation, neurofibrillary tangles, and accumulation of insoluble protein plaques. Together, our results shed new light upon the neurodegeneration observed in Munc18-1(-/-) mice and argue that this phenomenon shares parallels with neurodegenerative diseases.