Myelin basic protein is an RNA chaperone in microglial nuclear retro-transport

CNS oligodendrocytes generate myelin, an RNA-containing proteolipid substance that enhances axonal transmission. In multiple sclerosis (MS), myelin debris is phagocytosed by microglia (MG), and prior studies have detected myelin-derived mRNA in MG nuclei, suggesting a retrograde transport pathway. We report myelin basic protein (MBP) is a nucleic acid binding and trafficking protein. We found that retro-transport of myelin RNA into the MG nucleus was phagocytosis and importin dependent. Transcriptomic and proteomic analyses of MG nuclei revealed enrichment of myelin mRNAs and proteins, with MBP singularly detected in soluble and chromatin associated fractions. MBP bound mRNA with high affinity (Kd ≈ 0.30 nM) and was sufficient to facilitate MG RNA nuclear import in vitro and in vivo. Functionally, MBP mediated the delivery of small interfering RNAs for targeted knockdown of toll-like receptor 4. These findings indicate MBP as an RNA binding protein capable of MG nuclear import, providing insight into neuroinflammatory pathology of MS.