Department of Neurology, Section of Developmental Neurobiology, University Hospital Würzburg, Würzburg, Germany.
Institute of Neuronal Cell Biology, Technical University Munich, Munich, Germany.
Nat Commun. 2023 Oct 30;14(1):6911. doi: 10.1038/s41467-023-42570-2.
Axon degeneration and functional decline in myelin diseases are often attributed to loss of myelin but their relation is not fully understood. Perturbed myelinating glia can instigate chronic neuroinflammation and contribute to demyelination and axonal damage. Here we study mice with distinct defects in the proteolipid protein 1 gene that develop axonal damage which is driven by cytotoxic T cells targeting myelinating oligodendrocytes. We show that persistent ensheathment with perturbed myelin poses a risk for axon degeneration, neuron loss, and behavioral decline. We demonstrate that CD8 T cell-driven axonal damage is less likely to progress towards degeneration when axons are efficiently demyelinated by activated microglia. Mechanistically, we show that cytotoxic T cell effector molecules induce cytoskeletal alterations within myelinating glia and aberrant actomyosin constriction of axons at paranodal domains. Our study identifies detrimental axon-glia-immune interactions which promote neurodegeneration and possible therapeutic targets for disorders associated with myelin defects and neuroinflammation.
轴突变性和髓鞘疾病中的功能衰退通常归因于髓鞘的丧失，但它们之间的关系尚未完全阐明。受干扰的髓鞘形成胶质细胞会引发慢性神经炎症，并导致脱髓鞘和轴突损伤。在这里，我们研究了具有明显蛋白脂质蛋白 1 基因缺陷的小鼠，这些小鼠发生了由针对髓鞘少突胶质细胞的细胞毒性 T 细胞驱动的轴突损伤。我们表明，受干扰的髓鞘的持续包绕会导致轴突变性、神经元丧失和行为下降的风险。我们证明，当激活的小胶质细胞有效地使轴突脱髓鞘时，CD8 T 细胞驱动的轴突损伤不太可能进展为退行性变。从机制上讲，我们表明细胞毒性 T 细胞效应分子在髓鞘形成胶质细胞内诱导细胞骨架改变，并在轴突的连接蛋白区域引起异常的肌动球蛋白收缩。我们的研究确定了促进神经退行性变的有害轴突-胶质细胞-免疫相互作用，并为与髓鞘缺陷和神经炎症相关的疾病提供了可能的治疗靶点。
