中国神经再生研究(英文版) ›› 2016, Vol. 11 ›› Issue (7): 1029-1032.doi: 10.4103/1673-5374.187018

• 综述:神经损伤修复保护与再生 •    下一篇

Lim激酶在损伤导致的结构突触重塑中扮演双功能角色

  

  • 出版日期:2016-07-30 发布日期:2016-07-30
  • 基金资助:

    这项工作是由美国国立卫生研究院EY021542和F.M.柯比基金会支持

Lim kinase, a bi-functional effector in injury-induced structural plasticity of synapses

Weiwei Wang, Ellen Townes-Anderson*   

  1. Department of Pharmacology, Physiology and Neuroscience, New Jersey Medical School, Graduate School of Biomedical Sciences, Rutgers Biomedical and Health Sciences, Rutgers, The State University of New Jersey, Newark, NJ, USA
  • Online:2016-07-30 Published:2016-07-30
  • Contact: Ellen Townes-Anderson, Ph.D., andersel@njms.rutgers.edu.
  • Supported by:

    This work was supported by NIH grant EY021542 and the F.M. Kirby Foundation.

摘要:

规范的Rho家族(RhoA、Rac1和Cdc42)所发送的RhoGTPase信号能够在一定程度上调节肌动蛋白循环,从而在突触可塑性中扮演着重要角色。而且,通过使用RhoA对抗物等方法控制肌动蛋白细胞骨架,已经在治疗神经退行性疾病和促进中枢神经系统的轴突再生方面得到了成功例证。 Rho信号在视网膜感觉神经元的轴突和终端以及光感受器当中同样发挥着重要作用。光感受器可以显示疾病或损伤所引起的结构性突触可塑性,包括轴突萎缩、神经炎增生以及突触前静脉曲张。我们可以通过这些体外细胞和组织系统检查因损伤所导致的视网膜结构可塑性中的Rho通路。通过下游效应物Lim 激酶(LIMK)在各个通路间进行互联能够将神经退行性事件与神经再生性事件联系起来,开创了一种全新的治疗手段,单就视网膜损伤情况而言,通过这种新治疗方法,视力能够得以保留。有一种观点认为,LIMK活动会导致微管脱稳定化。例如,人们发现在人体上皮细胞中,LIMK可以渗入到微管中。降低LIMK活动性能够打断凝血酶介导的微管脱稳定化和肌动蛋白聚合过程,而通过ROCK 2激活可以降低LIMK微管蛋白,同时增强LIMK与肌动蛋白间的互动。因此,LIMK的另一个临床性优势就是它可以同时调节肌动蛋白和微管的动态。当然,我们还需要进行更多的研究来定义LIMK与其他细胞支架调节器(例如,Pak、ROCK 和 SSH)间短暂的空间关系,增加对LIMK在双功能结构性调节和临床治疗方面功能的了解。 

Abstract:

The structural plasticity of synaptic terminals contributes to normal nervous system function but also to neural degeneration, in the form of terminal retraction, and regeneration, due to process growth. Synaptic morphological change is mediated through the actin cytoskeleton, which is enriched in axonal and dendritic terminals. Whereas the three RhoGTPases, RhoA, Cdc42 and Rac, function as upstream signaling nodes sensitive to extracellular stimuli, LIMK-cofilin activity serves as a common downstream effector to up-regulate actin turnover, which is necessary for both polymerization and depolymerization. The dual effects of LIMK activity make LIMK a potential target of therapeutic intervention for injury-induced synaptic plasticity, as LIMK inhibition can stabilize actin cytoskeleton and preserve existing structure. This therapeutic benefit of LIMK inhibition has been demonstrated in animal models of injury-induced axon retraction and neuritic sprouting by rod photoreceptors. A better understanding of the regulation of LIMK-cofilin activity and the interaction with the microtubular cytoskeleton may open new ways to promote synaptic regeneration that can benefit neuronal degenerative disease.

Key words: LIMK, cofilin, RhoGTPases, actin turnover, structural plasticity, synaptic degeneration and regeneration