Department of Chemistry and Chemical Biology, Howard Hughes Medical Institute, Harvard University, Cambridge, United States.
Department of Physics, Howard Hughes Medical Institute, Harvard University, Cambridge, United States.
Elife. 2019 May 1;8:e38730. doi: 10.7554/eLife.38730.
Axon degeneration sculpts neuronal connectivity patterns during development and is an early hallmark of several adult-onset neurodegenerative disorders. Substantial progress has been made in identifying effector mechanisms driving axon fragmentation, but less is known about the upstream signaling pathways that initiate this process. Here, we investigate the behavior of the actin-spectrin-based Membrane-associated Periodic Skeleton (MPS), and effects of actin and spectrin manipulations in sensory axon degeneration. We show that trophic deprivation (TD) of mouse sensory neurons causes a rapid disassembly of the axonal MPS, which occurs prior to protein loss and independently of caspase activation. Actin destabilization initiates TD-related retrograde signaling needed for degeneration; actin stabilization prevents MPS disassembly and retrograde signaling during TD. Depletion of βII-spectrin, a key component of the MPS, suppresses retrograde signaling and protects axons against degeneration. These data demonstrate structural plasticity of the MPS and suggest its potential role in early steps of axon degeneration.
轴突变性在发育过程中塑造神经元连接模式，是几种成人发病的神经退行性疾病的早期标志。在识别驱动轴突碎片化的效应机制方面已经取得了重大进展，但关于启动这一过程的上游信号通路知之甚少。在这里，我们研究了基于肌动蛋白-血影蛋白的膜相关周期性骨架（MPS）的行为，以及肌动蛋白和血影蛋白操作对感觉轴突变性的影响。我们表明，小鼠感觉神经元的营养剥夺（TD）导致轴突 MPS 的快速解体，这发生在蛋白质丢失之前，并且独立于半胱天冬酶激活。肌动蛋白的不稳定性引发了 TD 相关的逆行信号，这是退化所必需的；肌动蛋白的稳定在 TD 期间防止 MPS 解体和逆行信号。βII-血影蛋白的耗竭，MPS 的关键组成部分，抑制逆行信号，并保护轴突免受退化。这些数据表明 MPS 的结构可塑性，并表明其在轴突退化的早期步骤中的潜在作用。
