Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, Australia.
School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
J Cell Biol. 2020 May 4;219(5). doi: 10.1083/jcb.201902001.
Most mammalian neurons have a narrow axon, which constrains the passage of large cargoes such as autophagosomes that can be larger than the axon diameter. Radial axonal expansion must therefore occur to ensure efficient axonal trafficking. In this study, we reveal that the speed of various large cargoes undergoing axonal transport is significantly slower than that of small ones and that the transit of diverse-sized cargoes causes an acute, albeit transient, axonal radial expansion, which is immediately restored by constitutive axonal contractility. Using live super-resolution microscopy, we demonstrate that actomyosin-II controls axonal radial contractility and local expansion, and that NM-II filaments associate with periodic F-actin rings via their head domains. Pharmacological inhibition of NM-II activity significantly increases axon diameter by detaching the NM-II from F-actin and impacts the trafficking speed, directionality, and overall efficiency of long-range retrograde trafficking. Consequently, prolonged NM-II inactivation leads to disruption of periodic actin rings and formation of focal axonal swellings, a hallmark of axonal degeneration.
大多数哺乳动物神经元的轴突很细，这限制了诸如自噬体等大型货物的通过，因为自噬体可能比轴突直径还大。因此，必须进行径向轴突扩张以确保有效的轴突运输。在这项研究中，我们揭示了各种大型货物在轴突运输中的速度明显慢于小型货物，而且不同大小的货物的运输会导致急性但短暂的轴突径向扩张，这种扩张会立即被组成型轴突收缩性所恢复。使用活细胞超分辨率显微镜，我们证明肌球蛋白-II 控制着轴突的径向收缩性和局部扩张，并且 NM-II 纤维通过其头部结构域与周期性的 F-actin 环结合。NM-II 活性的药理学抑制通过将 NM-II 从 F-actin 上分离出来，显著增加了轴突直径，并影响了长距离逆行运输的运输速度、方向性和整体效率。因此，NM-II 失活时间延长会导致周期性的 actin 环断裂，并形成轴突局部肿胀，这是轴突退化的一个标志。
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