An evolutionarily conserved function of glia is to provide metabolic and structural support for neurons. To identify molecules generated by glia and with vital functions for neurons, we used Drosophila melanogaster as a screening tool, and subsequently translated the findings to mice. We found that a cargo receptor operating in the secretory pathway of glia was essential to maintain axonal integrity by regulating iron buffering. Ferritin heavy chain was identified as the critical secretory cargo, required for the protection against iron-mediated ferroptotic axonal damage. In mice, ferritin heavy chain is highly expressed by oligodendrocytes and secreted by employing an unconventional secretion pathway involving extracellular vesicles. Disrupting the release of extracellular vesicles or the expression of ferritin heavy chain in oligodendrocytes causes neuronal loss and oxidative damage in mice. Our data point to a role of oligodendrocytes in providing an antioxidant defense system to support neurons against iron-mediated cytotoxicity.

神经胶质的进化保守功能是为神经元提供代谢和结构支持。为了鉴定由神经胶质产生的对神经元具有重要功能的分子，我们使用了黑腹果蝇作为筛选工具，随后将研究结果转化为小鼠。我们发现在神经胶质分泌途径中运行的货物受体对于通过调节铁缓冲来维持轴突完整性至关重要。铁蛋白重链被确定为关键的分泌货物，是防止铁介导的铁凋亡轴突损伤所必需的。在小鼠中，铁蛋白重链由少突胶质细胞高度表达，并通过涉及细胞外囊泡的非常规分泌途径分泌。破坏细胞外囊泡的释放或少突胶质细胞中铁蛋白重链的表达会导致小鼠神经元丢失和氧化损伤。我们的数据指出少突胶质细胞在提供抗氧化防御系统以支持神经元对抗铁介导的细胞毒性方面的作用。