J Neurosci：spectraplakins蛋白或为治疗神经变性疾病提供新思路

近日，来自曼彻斯特大学的研究者揭示了神经细胞如何向大脑“发电报”的内在分子机制，研究发现或许为神经变性疾病的治疗提供新思路，相关研究成果刊登在了国际著名杂志Journal of Neuroscience上。

研究团队表示，如果轴突不能正常发育，这就会导致先天性疾病，如智力损伤等。轴突的生长发育直接受其顶端的手型生长锥控制，研究者重点研究了生长锥移动的驱动器-细胞骨架，细胞骨架可以帮助细胞维持其基本结构形态，由很多肌动蛋白和微管结构组成。

研究者使用果蝇来分析肌动蛋白和微管结构如何结合形成自保骨架进而协调维持轴突的生长。多功能蛋白质spectraplakins对于轴突生长至关重要，其可以连接微管和肌动蛋白，帮助其定向延伸并且维持轴突的生长。如果这种连接缺失的话，微管网络就会紊乱进而导致轴突生长受到抑制。

研究者最后揭示，理解spectraplakins扮演的细胞功能对于生物医药研究至关重要，而且基于其在轴突生长中的作用，小鼠和人类中的spectraplakins蛋白质在很多过程中都很重要，比如在皮肤起泡、神经变性、突触形成一级神经元迁移等。

编译自：Cell Research Opens New Avenues in Combating Neurodegenerative Diseases

doi:10.1523/​JNEUROSCI.0416-12.2012
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Spectraplakins Promote Microtubule-Mediated Axonal Growth by Functioning As Structural Microtubule-Associated Proteins and EB1-Dependent +TIPs (Tip Interacting Proteins)

Juliana Alves-Silva1,*, Natalia Sánchez-Soriano1,*, Robin Beaven1, Melanie Klein1, Jill Parkin1, Thomas H. Millard1, Hugo J. Bellen2, Koen J. T. Venken2, Christoph Ballestrem1, Richard A. Kammerer1, and Andreas Prokop1

The correct outgrowth of axons is essential for the development and regeneration of nervous systems. Axon growth is primarily driven by microtubules. Key regulators of microtubules in this context are the spectraplakins, a family of evolutionarily conserved actin-microtubule linkers. Loss of function of the mouse spectraplakin ACF7 or of its close Drosophila homolog Short stop/Shot similarly cause severe axon shortening and microtubule disorganization. How spectraplakins perform these functions is not known. Here we show that axonal growth-promoting roles of Shot require interaction with EB1 (End binding protein) at polymerizing plus ends of microtubules. We show that binding of Shot to EB1 requires SxIP motifs in Shot's C-terminal tail (Ctail), mutations of these motifs abolish Shot functions in axonal growth, loss of EB1 function phenocopies Shot loss, and genetic interaction studies reveal strong functional links between Shot and EB1 in axonal growth and microtubule organization. In addition, we report that Shot localizes along microtubule shafts and stabilizes them against pharmacologically induced depolymerization. This function is EB1-independent but requires net positive charges within Ctail which essentially contribute to the microtubule shaft association of Shot. Therefore, spectraplakins are true members of two important classes of neuronal microtubule regulating proteins: +TIPs (tip interacting proteins; plus end regulators) and structural MAPs (microtubule-associated proteins). From our data we deduce a model that relates the different features of the spectraplakin C terminus to the two functions of Shot during axonal growth.