Abstract
Abstract Cognitive impairment in MS is associated with diffuse gray matter injury, which remains poorly understood. Given that axons span both white and gray matter regions, it’s possible that signals within these axons contribute to the spread of diffuse injury in the brain. We show that retrograde IFNg signaling in axons (in vitro human and murine) and demyelination (murine in vivo) cause transcriptional / translational changes in neuronal cell bodies. Chief among the candidate signaling pathways identified is ISGylation, a process whereby a multitude of cellular proteins are modified by the attachment of one or more ISG15 molecules. Using custom adeno-associated viral vectors we tested how altering ISGylation in neurons affects neuronal synaptic function and how it affects neuronal responsiveness to specific inflammatory factors in cell cultures. We also measured ISGylation in MS brain tissues to see if neuronal ISGylation correlates with gray matter injury in MS. We report early evidence that increased neuron ISGylation alters the composition of neuron-derived extracellular vesicles. Microglia treated with extracellular vesicles from neurons overexpressing ISGylation pathway genes exhibited morphology consistent with increased phagocytic activity and increased mRNA expression of inflammatory cytokines including: CCL2, IL1b, TNFa, iNOS, CXCL10, CCL5, and IL6. At this point, it is still unclear how these changes are related to gray matter pathology. However, it is possible that microglial activation by these vesicles is involved with driving synapse loss as activated microglia are known to be capable of stripping neuronal synapses.
Published Version
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