UC San Diego

Profiling binding repertoires of RNA binding proteins (RBPs) has uncovered how their intricate regulation shapes cellular function in health and disease. However many cell-type specific RBPs remain uncharacterized, especially within the CNS. We integrated our catalog of RBPs with cell-type annotations to identify microglial-specific RBPs and highlight ARID5A, an RBP previously implicated in peripheral immune cell RNA regulation, but not in microglia. We present integrated multi-omics analyses of ARID5A's RNA, DNA, and protein interactions, and leverage high-throughput sequencing and functional assays to uncover its RNA-mediated regulation of microglial functions. We show ARID5A binds RNA methylation sites, and regulates splicing and translation of transcripts integral to microglial functions. We found ARID5A modulates cytokine secretion, lysosome activity, and iron accumulation, as well as sensitivity to ferroptosis 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 not only emphasize the importance of profiling cell-type specific RBPs, but also highlight the potential of leveraging RBP-RNA interactions to restore dysregulated functions in neurodegeneration.