Genetically perturbed myelin as a risk factor for neuroinflammation-driven axon degeneration

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Axon degeneration and neurological dysfunction in myelin diseases is often attributed to loss of myelin. Perturbed myelinating glia can instigate chronic neuroinflammation and contribute to demyelination and axonal damage. We have previously shown in mice that distinct defects in the proteolipid protein 1 gene result in axonal damage which is largely driven by cytotoxic T cells targeting myelinating oligodendrocytes. Here we show in these mutants 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 aberrant cytoskeletal plasticity within myelinating glial processes and constriction of axons at paranodal domains. Our study identifies detrimental axon-glia interactions which promote neurodegeneration and possible therapeutic targets for disorders associated with myelin defects and neuroinflammation.