Kavli Affiliate: David Rowitch
| Authors: Guy LAM, Zhaoyang Xu, Adrien M Vaquie, Stavros Vagionitis, Michael Perry, Omar de Faria, Jr., Georgios Solomou, John H Stockley, Gemma C Girdler, Daniel Yamamoto, Juan A Oses, Qianqian Zhang, Gregory Jordan, Laura R Morcom, Jacob Stillman, Hani S Mousa, Alma Burlingame, Murray Stewart, Hauke B. Werner, Andras Lakatos, Harry Bulstrode, Dorothy P Schafer, Joanne L Jones, Ragnhildur Thora Karadottir and David H Rowitch
| Summary:
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.