Öztürk Zeynep, O'Kane Cahir J, Pérez-Moreno Juan José
Department of Genetics, University of Cambridge, Cambridge, United Kingdom.
Front Neurosci. 2020 Jan 29;14:48. doi: 10.3389/fnins.2020.00048. eCollection 2020.
The physical continuity of axons over long cellular distances poses challenges for their maintenance. One organelle that faces this challenge is endoplasmic reticulum (ER); unlike other intracellular organelles, this forms a physically continuous network throughout the cell, with a single membrane and a single lumen. In axons, ER is mainly smooth, forming a tubular network with occasional sheets or cisternae and low amounts of rough ER. It has many potential roles: lipid biosynthesis, glucose homeostasis, a Ca store, protein export, and contacting and regulating other organelles. This tubular network structure is determined by ER-shaping proteins, mutations in some of which are causative for neurodegenerative disorders such as hereditary spastic paraplegia (HSP). While axonal ER shares many features with the tubular ER network in other contexts, these features must be adapted to the long and narrow dimensions of axons. ER appears to be physically continuous throughout axons, over distances that are enormous on a subcellular scale. It is therefore a potential channel for long-distance or regional communication within neurons, independent of action potentials or physical transport of cargos, but involving its physiological roles such as Ca or organelle homeostasis. Despite its apparent stability, axonal ER is highly dynamic, showing features like anterograde and retrograde transport, potentially reflecting continuous fusion and breakage of the network. Here we discuss the transport processes that must contribute to this dynamic behavior of ER. We also discuss the model that these processes underpin a homeostatic process that ensures both enough ER to maintain continuity of the network and repair breaks in it, but not too much ER that might disrupt local cellular physiology. Finally, we discuss how failure of ER organization in axons could lead to axon degenerative diseases, and how a requirement for ER continuity could make distal axons most susceptible to degeneration in conditions that disrupt ER continuity.
轴突在长细胞距离上的物理连续性对其维持构成了挑战。面临这一挑战的一种细胞器是内质网（ER）；与其他细胞内细胞器不同，内质网在整个细胞中形成一个物理上连续的网络，具有单一的膜和单一的管腔。在轴突中，内质网主要是光滑的，形成一个管状网络，偶尔有片层或潴泡，粗面内质网含量较低。它有许多潜在作用：脂质生物合成、葡萄糖稳态、钙储存、蛋白质输出以及与其他细胞器接触和调节。这种管状网络结构由内质网塑形蛋白决定，其中一些蛋白的突变是遗传性痉挛性截瘫（HSP）等神经退行性疾病的病因。虽然轴突内质网在其他情况下与管状内质网网络有许多共同特征，但这些特征必须适应轴突的长而窄的尺寸。内质网在整个轴突上似乎是物理连续的，在亚细胞尺度上这是一个巨大的距离。因此，它是神经元内长距离或区域通信的潜在通道，独立于动作电位或货物的物理运输，但涉及钙或细胞器稳态等生理作用。尽管轴突内质网看似稳定，但它具有高度动态性，表现出顺行和逆行运输等特征，这可能反映了网络的持续融合和断裂。在这里，我们讨论了必须有助于内质网这种动态行为的运输过程。我们还讨论了这些过程支持一种稳态过程的模型，该稳态过程既能确保有足够的内质网来维持网络的连续性并修复其中的断裂处，又不会有过多的内质网可能破坏局部细胞生理功能。最后，我们讨论了轴突内质网组织的失败如何导致轴突退行性疾病，以及内质网连续性的要求如何使远端轴突在破坏内质网连续性的情况下最易发生退化。
