GSE290755

Summary

RNA binding proteins (RBPs) shape cellular function in health and disease. However, the function of RBPs expressed specifically in the central nervous system (CNS) remain uncharacterized. Within the CNS, we identify ARID5A as a microglial-specific RBP and integrate multi-omics analyses of ARID5A's RNA, DNA, and protein interactions to uncover its RNA-mediated regulation of microglial functions. We show ARID5A regulates the splicing and translation of its RNA targets, many of which are integral to microglial functions. We find ARID5A modulates cytokine secretion, lysosome activity, and iron accumulation, as well as ferroptosis sensitivity in microglia and co-cultured neurons. We illustrate the neuroprotective potential of ARID5A modulation, in which knockdown restored dysregulated functions in TREM2 mutant microglia. Our results highlight the potential of leveraging ARID5A-RNA interactions to restore dysregulated pathways in neurodegeneration.