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

LAM, G.; Xu, Z.; Vaquie, A. M.; Vagionitis, S. P.; Perry, M.; de Faria, O.; Solomou, G.; Stockley, J. H.; Girdler, G. C.; Yamamoto, D.; Oses, J. A.; Zhang, Q.; Jordan, G.; Morcom, L. R.; Stillman, J.; Mousa, H. S.; Burlingame, A.; Stewart, M.; Werner, H. B.; Lakatos, A.; Bulstrode, H.; Schafer, D. P.; Jones, J. L.; Karadottir, R. T.; Rowitch, D. H.

doi:10.64898/2026.05.14.725089

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bioRxiv · 10.64898/2026.05.14.725089

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

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Abstract

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 {approx} 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.

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LAM, G., Xu, Z., Vaquie, A. M., Vagionitis, S. P., Perry, M., de Faria, O., Solomou, G., Stockley, J. H., Girdler, G. C., Yamamoto, D., Oses, J. A., Zhang, Q., Jordan, G., Morcom, L. R., Stillman, J., Mousa, H. S., Burlingame, A., Stewart, M., Werner, H. B., Lakatos, A., Bulstrode, H., Schafer, D. P., Jones, J. L., Karadottir, R. T., Rowitch, D. H.. 2026-05-16. Myelin basic protein is an RNA chaperone in microglial nuclear retro-transport. https://doi.org/10.64898/2026.05.14.725089

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