Fuchs, U.; Schroeder, S.; Pena, T.; Krueger, D. M.; Burkhardt, S.; Schuetz, A.-L.; Sananbenesi, F.; Fischer, A.

Long non-coding RNAs (lncRNAs) are increasingly recognized as regulators of cellular identity and disease associated gene expression programs, yet their role in astrocyte reactivity remains poorly understood. Here, we profiled lncRNA expression in primary mouse astrocytes exposed to inflammatory activation paradigms that model microglia driven signaling. This identified a conserved set of activation responsive lncRNAs, among which Gm16685 emerged as one of the most strongly induced candidates. Gm16685 and its human homolog MITA1 were enriched in the nucleus, and MITA1 expression was increased in selected human datasets from Alzheimer's disease, Parkinson's disease and frontotemporal dementia patients. Functional depletion of Gm16685 attenuated inflammatory gene expression and several activation associated astrocyte phenotypes, including reactive oxygen species production, glutamate handling, phagocytic activity and proliferation. Time-resolved transcriptomic analysis indicated that Gm16685 is required for the timely induction of inflammatory response genes. Mechanistically, Gm16685/MITA1 interacted with the RNA binding protein PCBP2, and Gm16685 depletion was associated with reduced PCBP2 protein abundance, altered splicing of Inhibitor of NF-{kappa}B Kinase Subunit Beta (IKK{beta}) and a shift in downstream inflammatory signaling. Together, our findings identify Gm16685/MITA1 as a conserved lncRNA regulator of astrocyte reactivity and suggest that non-coding RNA dependent control of RNA binding proteins contributes to inflammatory signaling in neurodegenerative disease relevant contexts.