Axonopathy Is Associated with Complex Axonal Transport Defects in a Model of Multiple Sclerosis
Axonopathy Is Associated with Complex Axonal Transport Defects in a Model of Multiple Sclerosis
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DOI：
10.1111/j.1750-3639.2011.00541.x
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发表时间：
2012-07
期刊：
影响因子：
6.4
通讯作者：
M. Kreutzer;F. Seehusen;R. Kreutzer;K. Pringproa;M. Kummerfeld;P. Claus;U. Deschl;Arno Kalkul;A. Beineke;W. Baumgärtner;R. Ulrich
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文献类型：
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作者：
M. Kreutzer;F. Seehusen;R. Kreutzer;K. Pringproa;M. Kummerfeld;P. Claus;U. Deschl;Arno Kalkul;A. Beineke;W. Baumgärtner;R. Ulrich
多发性硬化症(MS)是一种以髓鞘和轴突病理为特征的炎症性和神经退行性疾病。在MS的病毒模型中，我们测试了轴索病的发生和发展是否建立在神经丝运输受损的基础上。应用基因芯片分析、光学显微镜、电子共聚焦显微镜和激光共聚焦显微镜等技术，对小鼠脑脊髓炎病毒(TMEV)感染和模拟感染的小鼠脊髓和神经母细胞瘤N1E-115细胞进行了分析。TMEV感染后体内非磷酸化神经细丝的轴突堆积表现为轴突交通的损伤，包括Kinesin家族成员5A、动力蛋白细胞质重链1、tau-1和β-微管蛋白III的表达下调。此外，还观察到蛋白质代谢的变化。在体外，感染TMEV的N1E-115细胞出现了类似于体内变化的串联重复肿胀。此外，涉及烟酰胺腺嘌呤二核苷酸缺失的潜在轴突自毁程序的假说得到了分子研究结果的支持。结果表明，TME内神经丝堆积主要是其轴突运输机制失调、神经丝磷酸化和蛋白质代谢受损的结果。目前的发现使我们能够更准确地了解炎性退行性疾病中轴突病变的启动和发展的复杂相互作用。
Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease characterized by myelin and axonal pathology. In a viral model of MS, we tested whether axonopathy initiation and development are based on an impaired transport of neurofilaments. Spinal cords of Theiler's murine encephalomyelitis virus (TMEV)‐infected and mock‐infected mice and TMEV infected neuroblastoma N1E‐115 cells were analyzed by microarray analysis, light microscopy and electron and laser confocal microscopy. In vivo axonal accumulation of non‐phosphorylated neurofilaments after TMEV infection revealed a temporal development caused by the impairments of the axonal traffic consisting of the downregulation of kinesin family member 5A, dynein cytoplasmic heavy chain 1, tau‐1 and β‐tubulin III expression. In addition, alterations of the protein metabolism were also noticed. In vitro, the TMEV‐infected N1E‐115 cells developed tandem‐repeated swellings similar to in vivo alterations. Furthermore, the hypothesis of an underlying axonal self‐destruction program involving nicotinamide adenine dinucleotide depletion was supported by molecular findings. The obtained data indicate that neurofilament accumulation in TME is mainly the result of dysregulation of their axonal transport machinery and impairment of neurofilament phosphorylation and protein metabolism. The present findings allow a more precise understanding of the complex interactions responsible for initiation and development of axonopathies in inflammatory degenerative diseases.