Gentil Benoit J, Tibshirani Michael, Durham Heather D
Department of Neurology/Neurosurgery and Montreal Neurological Institute, McGill University, Montreal, QC, H3A 2B4, Canada,
Cell Tissue Res. 2015 Jun;360(3):609-20. doi: 10.1007/s00441-014-2082-7. Epub 2015 Jan 8.
Neurons are extremely polarised cells in which the cytoskeleton, composed of microtubules, microfilaments and neurofilaments, plays a crucial role in maintaining structure and function. Neurofilaments, the 10-nm intermediate filaments of neurons, provide structure and mechanoresistance but also provide a scaffolding for the organization of the nucleus and organelles such as mitochondria and ER. Disruption of neurofilament organization and expression or metabolism of neurofilament proteins is characteristic of certain neurological syndromes including Amyotrophic Lateral Sclerosis, Charcot-Marie-Tooth sensorimotor neuropathies and Giant Axonal Neuropathy. Microfluorometric live imaging techniques have been instrumental in revealing the dynamics of neurofilament assembly and transport and their functions in organizing intracellular organelle networks. The insolubility of neurofilament proteins has limited identifying interactors by conventional biochemical techniques but yeast two-hybrid experiments have revealed new roles for oligomeric, nonfilamentous structures including vesicular trafficking. Although having long half-lives, new evidence points to degradation of subunits by the ubiquitin-proteasome system as a mechanism of normal turnover. Although certain E3-ligases ubiquitinating neurofilament proteins have been identified, the overall process of neurofilament degradation is not well understood. We review these mechanisms of neurofilament homeostasis and abnormalities in motor neuron and peripheral nerve disorders. Much remains to discover about the disruption of processes that leads to their pathological aggregation and accumulation and the relevance to pathogenesis. Understanding these mechanisms is crucial for identifying novel therapeutic strategies.
神经元是极具极性的细胞，其细胞骨架由微管、微丝和神经丝组成，在维持结构和功能方面起着关键作用。神经丝是神经元的10纳米中间丝，不仅提供结构和机械抗性，还为细胞核以及线粒体和内质网等细胞器的组织提供支架。神经丝组织的破坏以及神经丝蛋白的表达或代谢异常是某些神经综合征的特征，包括肌萎缩侧索硬化症、夏科-马里-图斯感觉运动神经病和巨大轴突神经病。显微荧光活体成像技术有助于揭示神经丝组装和运输的动态过程及其在组织细胞内细胞器网络中的功能。神经丝蛋白的不溶性限制了通过传统生化技术鉴定相互作用分子，但酵母双杂交实验揭示了包括囊泡运输在内的寡聚、非丝状结构的新作用。尽管神经丝蛋白半衰期较长，但新证据表明泛素-蛋白酶体系统对亚基的降解是正常周转的一种机制。虽然已经鉴定出某些泛素化神经丝蛋白的E3连接酶，但神经丝降解的整体过程仍未完全了解。我们综述了神经丝稳态的这些机制以及运动神经元和周围神经疾病中的异常情况。关于导致其病理性聚集和积累的过程破坏及其与发病机制的相关性，仍有许多有待发现。了解这些机制对于确定新的治疗策略至关重要。
