Spastin interacts with the centrosomal protein NA14, and is enriched in the spindle pole, the midbody and the distal axon
Spastin interacts with the centrosomal protein NA14, and is enriched in the spindle pole, the midbody and the distal axon
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DOI：
10.1093/hmg/ddh223
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发表时间：
2004-09-15
影响因子：
3.5
通讯作者：
Rugarli, EI
中科院分区：
文献类型：
--
作者：
Errico, A;Claudiani, P;Rugarli, EI
遗传性痉挛性截瘫（HSP）的特点是中枢神经系统最长轴突，皮质脊髓束的特异性逆行变性。常染色体显性病例中最常见的基因是SPG4，它编码spastin，一种属于AAA家族的三磷酸腺苷酶。AAA蛋白被认为是通过蛋白质复合物的能量依赖性重排来发挥其功能的。这些蛋白的复合功能是通过它们与调节因子和适应蛋白的结合来指导的，这些调节因子和适应蛋白将其活性靶向到体内的特定途径中。我们之前发现过表达的spastin与微管动态相互作用并显示微管切断活性。在这里，我们证明了spastin在含有动态微管的细胞区域富集。在细胞分裂过程中，spastin存在于纺锤极、中央纺锤体和中间体，而在永生化运动神经元中，spastin富集于远端轴突和分支点。此外，spastin与中心体蛋白NA14相互作用，并与中心体标记物γ -微管蛋白共同分离。与NA14结合所需区域的缺失破坏了spastin与微管的相互作用，这表明NA14可能是在中心体上靶向spastin活性的重要适配器。这些数据有力地证明了spastin在细胞骨架重排和动力学中起作用，并为HSP中运动轴突的退化提供了一个有吸引力的解释。
Hereditary spastic paraplegia (HSP) is characterized by the specific retrograde degeneration of the longest axons in the central nervous system, the corticospinal tracts. The gene most frequently involved in autosomal dominant cases of this disease, SPG4, encodes spastin, an ATPase belonging to the AAA family. AAA proteins are thought to exert their function by the energy-dependent rearrangement of protein complexes. The composite function of these proteins is directed by their binding to regulatory factors and adaptor proteins that target their activity into specific pathways in vivo. We previously found that overexpressed spastin interacts dynamically with microtubules and displays microtubule-severing activity. Here, we demonstrate that spastin is enriched in cell regions containing dynamic microtubules. During cell division spastin is found in the spindle pole, the central spindle and the midbody, whereas in immortalized motoneurons it is enriched in the distal axon and the branching points. Furthermore, spastin interacts with the centrosomal protein NA14, and co-fractionates with gamma-tubulin, a centrosomal marker. Deletion of the region required for binding to NA14 disrupts spastin interaction with microtubules, suggesting that NA14 may be an important adaptor to target spastin activity at the centrosome. These data strongly argue that spastin plays a role in cytoskeletal rearrangements and dynamics, and provide an attractive explanation for the degeneration of motor axons in HSP.