Roselló-Busquets Cristina, de la Oliva Natalia, Martínez-Mármol Ramón, Hernaiz-Llorens Marc, Pascual Marta, Muhaisen Ashraf, Navarro Xavier, Del Valle Jaume, Soriano Eduardo
Department of Cell Biology, Physiology and Immunology, Faculty of Biology, Institute of Neurosciences, University of Barcelona, Barcelona, Spain.
Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain.
Front Cell Neurosci. 2019 Feb 12;13:40. doi: 10.3389/fncel.2019.00040. eCollection 2019.
Axonal growth during normal development and axonal regeneration rely on the action of many receptor signaling systems and complexes, most of them located in specialized raft membrane microdomains with a precise lipid composition. Cholesterol is a component of membrane rafts and the integrity of these structures depends on the concentrations present of this compound. Here we explored the effect of cholesterol depletion in both developing neurons and regenerating axons. First, we show that cholesterol depletion in developing neurons from the central and peripheral nervous systems increases the size of growth cones, the density of filopodium-like structures and the number of neurite branching points. Next, we demonstrate that cholesterol depletion enhances axonal regeneration after axotomy both in a microfluidic system using dissociated hippocampal neurons and in a slice-coculture organotypic model of axotomy and regeneration. Finally, using axotomy experiments in the sciatic nerve, we also show that cholesterol depletion favors axonal regeneration . Importantly, the enhanced regeneration observed in peripheral axons also correlated with earlier electrophysiological responses, thereby indicating functional recovery following the regeneration. Taken together, our results suggest that cholesterol depletion is able to promote axonal growth in developing axons and to increase axonal regeneration and both in the central and peripheral nervous systems.
正常发育过程中的轴突生长以及轴突再生依赖于许多受体信号系统和复合物的作用，其中大多数位于具有精确脂质组成的特殊脂筏膜微结构域中。胆固醇是膜脂筏的一个组成部分，这些结构的完整性取决于该化合物的现有浓度。在此，我们探究了胆固醇耗竭对发育中的神经元和再生轴突的影响。首先，我们发现中枢神经系统和外周神经系统中发育神经元的胆固醇耗竭会增加生长锥的大小、丝状伪足样结构的密度以及神经突分支点的数量。接下来，我们证明，在使用解离海马神经元的微流控系统以及轴突切断和再生的脑片共培养器官型模型中，胆固醇耗竭均能增强轴突切断后的轴突再生。最后，通过坐骨神经的轴突切断实验，我们还表明胆固醇耗竭有利于轴突再生。重要的是，在外周轴突中观察到的增强的再生也与更早的电生理反应相关，从而表明再生后的功能恢复。综上所述，我们的结果表明，胆固醇耗竭能够促进发育中轴突的轴突生长，并增加中枢神经系统和外周神经系统中的轴突再生。
