Inflammation and dysregulation of the immune system are hallmarks of several neurodegenerative diseases. An activated immune response is considered to be the cause of myelin breakdown in demyelinating disorders. In the peripheral nervous system (PNS), myelin can be degraded in an autophagy-dependent manner directly by Schwann cells or by macrophages, which are modulated by T-lymphocytes. Here, we show that the NF-κB activator Pleckstrin homology containing family member 5 (Plekhg5) is involved in the regulation of both Schwann cell autophagy and recruitment of T-lymphocytes in peripheral nerves during motoneuron disease. Plekhg5-deficient mice show defective axon/Schwann cell units characterized by myelin infoldings in peripheral nerves. Even at late stages, Plekhg5-deficient mice do not show any signs of demyelination and inflammation. Using RNAseq, we identified a transcriptional signature for an impaired immune response in sciatic nerves, which manifested in a reduced number of CD4⁺ and CD8⁺ T-cells. These findings identify Plekhg5 as a promising target to impede myelin breakdown in demyelinating PNS disorders.

免疫系统的炎症和调节异常是几种神经退行性疾病的标志。活化的免疫应答被认为是脱髓鞘疾病中髓磷脂分解的原因。在周围神经系统（PNS）中，髓鞘磷脂可以直接被雪旺氏细胞或巨噬细胞以自噬依赖性方式降解，而雪旺氏细胞或巨噬细胞受T淋巴细胞的调节。在这里，我们显示包含运动神经元疾病期间，家族成员5（Plekhg5）的NF-κB激活素Pleckstrin同源性参与雪旺细胞自噬的调节和周围神经T淋巴细胞的募集。Plekhg5缺陷的小鼠显示出缺陷的轴突/雪旺细胞单位，其特征在于外周神经中的髓磷脂折叠。即使在后期Plekhg5缺陷的小鼠没有任何脱髓鞘和炎症迹象。使用RNAseq，我们鉴定出坐骨神经免疫应答受损的转录特征，表现为CD4 ⁺和CD8 ⁺ T细胞数量减少。这些发现确定Plekhg5是阻止脱髓鞘性PNS疾病中髓磷脂降解的有希望的靶标。