Wang Weiwei, Townes-Anderson Ellen
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.
Neural Regen Res. 2016 Jul;11(7):1029-32. doi: 10.4103/1673-5374.187018.
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.
突触终末的结构可塑性有助于正常的神经系统功能，但也会导致神经退行性变，表现为终末回缩，以及由于突起生长而出现的再生。突触形态变化是由肌动蛋白细胞骨架介导的，其在轴突和树突终末中含量丰富。三种RhoGTP酶，即RhoA、Cdc42和Rac，作为对细胞外刺激敏感的上游信号节点发挥作用，而LIMK-丝切蛋白活性作为一个共同的下游效应器，可上调肌动蛋白周转，这对于聚合和解聚都是必需的。LIMK活性的双重作用使LIMK成为损伤诱导的突触可塑性治疗干预的潜在靶点，因为抑制LIMK可以稳定肌动蛋白细胞骨架并保留现有结构。在损伤诱导的轴突回缩和视杆光感受器神经突萌发的动物模型中，已经证明了抑制LIMK的这种治疗益处。更好地理解LIMK-丝切蛋白活性的调节以及与微管细胞骨架的相互作用，可能会开辟促进突触再生的新途径，从而使神经元退行性疾病受益。
