Axon degeneration is a hallmark of many neurodegenerative disorders. The current assumption is that the decision of injured axons to degenerate is cell-autonomously regulated. Here we show that Schwann cells (SCs), the glia of the peripheral nervous system, protect injured axons by virtue of a dramatic glycolytic upregulation that arises in SCs as an inherent adaptation to axon injury. This glycolytic response, paired with enhanced axon–glia metabolic coupling, supports the survival of axons. The glycolytic shift in SCs is largely driven by the metabolic signaling hub, mammalian target of rapamycin complex 1, and the downstream transcription factors hypoxia-inducible factor 1-alpha and c-Myc, which together promote glycolytic gene expression. The manipulation of glial glycolytic activity through this pathway enabled us to accelerate or delay the degeneration of perturbed axons in acute and subacute rodent axon degeneration models. Thus, we demonstrate a non-cell-autonomous metabolic mechanism that controls the fate of injured axons.

轴突变性是许多神经退行性疾病的标志。目前的假设是受损轴突退化的决定是细胞自主调节的。在这里，我们展示了周围神经系统的神经胶质雪旺细胞 (SCs)，通过在 SCs 中作为对轴突损伤的固有适应而出现的显着糖酵解上调来保护受伤的轴突。这种糖酵解反应与增强的轴突-神经胶质代谢偶联相结合，支持轴突的存活。SCs 中的糖酵解转变主要由代谢信号中心、雷帕霉素复合物 1 的哺乳动物靶标以及下游转录因子缺氧诱导因子 1-α 和 c-Myc 驱动，它们共同促进糖酵解基因的表达。通过该途径操纵神经胶质糖酵解活性使我们能够加速或延迟急性和亚急性啮齿动物轴突退化模型中受扰动的轴突的退化。因此，我们展示了一种控制受损轴突命运的非细胞自主代谢机制。