Wishart Thomas M, Pemberton Helen N, James Sally R, McCabe Chris J, Gillingwater Thomas H
Centre for Integrative Physiology, University of Edinburgh Medical School, Edinburgh, UK.
Genome Biol. 2008;9(6):R101. doi: 10.1186/gb-2008-9-6-r101. Epub 2008 Jun 20.
Altered neuronal vulnerability underlies many diseases of the human nervous system, resulting in degeneration and loss of neurons. The neuroprotective slow Wallerian degeneration (Wlds) mutation delays degeneration in axonal and synaptic compartments of neurons following a wide range of traumatic and disease-inducing stimuli, providing a powerful experimental tool with which to investigate modulation of neuronal vulnerability. Although the mechanisms through which Wlds confers neuroprotection remain unclear, a diverse range of downstream modifications, incorporating several genes/pathways, have been implicated. These include the following: elevated nicotinamide adenine dinucleotide (NAD) levels associated with nicotinamide mononucleotide adenylyltransferase 1 (Nmnat1; a part of the chimeric Wlds gene); altered mRNA expression levels of genes such as pituitary tumor transforming gene 1 (Pttg1); changes in the location/activity of the ubiquitin-proteasome machinery via binding to valosin-containing protein (VCP/p97); and modified synaptic expression of proteins such as ubiquitin-activating enzyme E1 (Ube1).
Wlds expression in mouse cerebellum and HEK293 cells induced robust increases in a broad spectrum of cell cycle-related genes. Both NAD-dependent and Pttg1-dependent pathways were responsible for mediating different subsets of these alterations, also incorporating changes in VCP/p97 localization and Ube1 expression. Cell proliferation rates were not modified by Wlds, suggesting that later mitotic phases of the cell cycle remained unaltered. We also demonstrate that Wlds concurrently altered endogenous cell stress pathways.
We report a novel cellular phenotype in cells with altered neuronal vulnerability. We show that previous reports of diverse changes occurring downstream from Wlds expression converge upon modifications in cell cycle status. These data suggest a strong correlation between modified cell cycle pathways and altered vulnerability of axonal and synaptic compartments in postmitotic, terminally differentiated neurons.
神经元易损性改变是许多人类神经系统疾病的基础，会导致神经元变性和丧失。神经保护性慢沃勒变性（Wlds）突变可延缓神经元轴突和突触区室在多种创伤和疾病诱导刺激后的变性，为研究神经元易损性的调节提供了一个强大的实验工具。尽管Wlds赋予神经保护作用的机制尚不清楚，但已涉及多种下游修饰，包括几个基因/途径。这些包括：与烟酰胺单核苷酸腺苷酸转移酶1（Nmnat1；嵌合Wlds基因的一部分）相关的烟酰胺腺嘌呤二核苷酸（NAD）水平升高；垂体肿瘤转化基因1（Pttg1）等基因的mRNA表达水平改变；通过与含缬酪蛋白（VCP/p97）结合改变泛素-蛋白酶体机制的位置/活性；以及泛素激活酶E1（Ube1）等蛋白质的突触表达改变。
Wlds在小鼠小脑和HEK293细胞中的表达诱导了广泛的细胞周期相关基因的强烈增加。NAD依赖性和Pttg1依赖性途径均负责介导这些改变的不同子集，还包括VCP/p97定位和Ube1表达的变化。细胞增殖率未被Wlds改变，这表明细胞周期的后期有丝分裂阶段保持不变。我们还证明Wlds同时改变了内源性细胞应激途径。
我们报告了一种神经元易损性改变的细胞中的新细胞表型。我们表明先前关于Wlds表达下游发生的各种变化的报道都集中在细胞周期状态的改变上。这些数据表明，在有丝分裂后、终末分化的神经元中，修饰的细胞周期途径与轴突和突触区室易损性改变之间存在很强的相关性。
