multiple complement components that help to drive synapse degeneration33. In acute relapsing and remitting MS, we also observed C3-expressing A1s in demyelinating plaques. This suggests the possibility that demyelinating lesions, which generally also contain unmyelinated axons and OPCs, fail to remyelinate because A1s inhibit OPC proliferation and differentiation and kill any newly-generated oligodendrocytes (in the chronic progressive phase of the disease A1s might also drive axon degeneration). Would drugs that prevent or revert A1 formation or block action of the A1 neurotoxin prevent neurodegeneration in these diseases and stimulate spontaneous remyelination in MS and new synapse formation in diseases such as Alzheimer’s? Similarly, would drugs that prevent or revert A1s save axotomized CNS neurons after spinal cord injury and promote regeneration by stimulating growth and allowing these astrocytes to clear myelin debris? Future studies should test these possibilities in animal models, as antibody drugs that inhibit human IL-1α and TNFα are already FDA approved and in use for other medical conditions. Lastly, do epithelial cells outside the CNS undergo an A1-like neurotoxic transformation after injury or disease that contributes to cell death of non-CNS cell types, for instance beta islet cells in diabetes?
