Neuron-glia interactions underlie ALS-like axonal cytoskeletal pathology
Neuron-glia interactions underlie ALS-like axonal cytoskeletal pathology
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DOI：
10.1016/j.neurobiolaging.2009.04.004
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发表时间：
2011-03-01
影响因子：
4.2
通讯作者：
Vickers, J. C.
中科院分区：
文献类型：
--
作者：
King, A. E.;Dickson, T. C.;Vickers, J. C.
肌萎缩侧索硬化症（ALS）是一种破坏性的疾病，涉及由于运动神经元变性而导致的运动丧失。研究表明，在ALS中，轴突功能障碍先于运动神经元的死亡。在病理学上，ALS的特征在于运动神经元的轴突内的神经丝索（球状体）。然而，这种轴突病的原因和可能导致轴突功能障碍是未知的。使用一种新的模型培养的小鼠运动神经元，我们已经确定，这些神经元易受近端轴突病变，这是有关的胶质环境。这种轴突病变在形态学和神经化学上与SOD1（G93A）转基因小鼠中数月内形成的球状体表现出显著的相似性。局灶性泛素化，以及神经丝和微管的扰动，发生在轴突球状体样selling在体外，和可视化的线粒体动力学表明，轴突病导致受损的轴突运输。这些数据提供了强有力的证据，非神经元细胞参与ALS的轴突功能障碍。这种细胞培养模型可能有利于开发针对轴突保存的治疗干预措施。(C)2009年由Elsevier Inc.出版
Amyotrophic lateral sclerosis (ALS) is a devastating disorder involving loss of movement due to degeneration of motor neurons. Studies suggest that in ALS axonal dysfunction precedes the death of motor neurons. Pathologically, ALS is characterized by neurofilamentous swellings (spheroids) within the axons of motor neurons. However, the causes of this axonopathy and possible resulting axonal dysfunction are not known. Using a novel model of cultured mouse motor neurons, we have determined that these neurons are susceptible to proximal axonopathy, which is related to the glial environment. This axonopathy showed remarkable similarity, both morphologically and neurochemically, to spheroids that develop over months in SOD1(G93A) transgenic mice. Focal ubiquitination, as well as perturbations of neurofilaments and microtubules, occurred in the axonal spheroid-like swellings in vitro, and visualization of mitochondrial dynamics demonstrated that axonopathy resulted in impaired axonal transport. These data provide strong evidence for the involvement of non-neuronal cells in axonal dysfunction in ALS. This cell culture model may be of benefit for the development of therapeutic interventions directed at axonal preservation. (C) 2009 Published by Elsevier Inc.