Smith Gaynor, Sweeney Sean T, O'Kane Cahir J, Prokop Andreas
Cardiff University, School of Medicine, College of Biomedical and Life Sciences, Cardiff, United Kingdom.
Department of Biology, University of York and York Biomedical Research Institute, York, United Kingdom.
Front Neurosci. 2023 Jul 26;17:1236815. doi: 10.3389/fnins.2023.1236815. eCollection 2023.
Axons are processes of neurons, up to a metre long, that form the essential biological cables wiring nervous systems. They must survive, often far away from their cell bodies and up to a century in humans. This requires self-sufficient cell biology including structural proteins, organelles, and membrane trafficking, metabolic, signalling, translational, chaperone, and degradation machinery-all maintaining the homeostasis of energy, lipids, proteins, and signalling networks including reactive oxygen species and calcium. Axon maintenance also involves specialised cytoskeleton including the cortical actin-spectrin corset, and bundles of microtubules that provide the highways for motor-driven transport of components and organelles for virtually all the above-mentioned processes. Here, we aim to provide a conceptual overview of key aspects of axon biology and physiology, and the homeostatic networks they form. This homeostasis can be derailed, causing axonopathies through processes of ageing, trauma, poisoning, inflammation or genetic mutations. To illustrate which malfunctions of organelles or cell biological processes can lead to axonopathies, we focus on axonopathy-linked subcellular defects caused by genetic mutations. Based on these descriptions and backed up by our comprehensive data mining of genes linked to neural disorders, we describe the 'dependency cycle of local axon homeostasis' as an integrative model to explain why very different causes can trigger very similar axonopathies, providing new ideas that can drive the quest for strategies able to battle these devastating diseases.
轴突是神经元的突起，长达一米，是构成神经系统的基本生物电缆。它们必须存活，通常远离细胞体，在人类中可达一个世纪之久。这需要自给自足的细胞生物学，包括结构蛋白、细胞器、膜运输、代谢、信号传导、翻译、分子伴侣和降解机制——所有这些都维持着能量、脂质、蛋白质以及包括活性氧和钙在内的信号网络的稳态。轴突维持还涉及特殊的细胞骨架，包括皮质肌动蛋白 - 血影蛋白束腰，以及微管束，这些微管束为几乎所有上述过程中由分子马达驱动的成分和细胞器运输提供了通道。在这里，我们旨在对轴突生物学和生理学的关键方面以及它们形成的稳态网络进行概念性概述。这种稳态可能会被破坏，通过衰老、创伤、中毒、炎症或基因突变等过程导致轴突病变。为了说明细胞器或细胞生物学过程的哪些故障会导致轴突病变，我们重点关注由基因突变引起的与轴突病变相关的亚细胞缺陷。基于这些描述，并通过我们对与神经疾病相关基因的全面数据挖掘作为支持，我们将“局部轴突稳态的依赖循环”描述为一种综合模型，以解释为什么非常不同的原因会引发非常相似的轴突病变，为推动寻找能够对抗这些毁灭性疾病的策略提供新的思路。
