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Upf2-mediated inhibition of nonsense mediated decay causes memory and social deficits by activating the immune response

ABSTRACT: Nonsense-mediated decay (NMD) is an evolutionarily conserved surveillance mechanism that targets mRNAs undergoing premature translation termination for rapid degradation as well as normal physiological transcripts. From yeast to humans, NMD requires the function of three conserved Up-frameshift (Upf) factors (Upf1, Upf2, Upf3). Interestingly, in humans, mutations in UPF2 and UPF3B are associated with intellectual disability and autism spectrum disorder (ASD). However, the neurobiological mechanism by which deficient NMD leads to neurodevelopmental disorders remains unknown. Consequently, no treatment is currently available. Here we report that mice lacking Upf2 in the murine forebrain (Upf2 fb-KO mice) show endophenotypes associated with ASD and deficits in learning and memory. In addition, Upf2-mediated deficient NMD leads to abnormal long-term potentiation (LTP) in the hippocampus. Like patients with mutations in UPF2, Upf2 fb-KO mice showed neuroanatomical abnormalities including a smaller corpus callosum. Surprisingly, transcriptomic analysis revealed elevated mRNA expression of immune-related genes in the hippocampus of Upf2-fb-KO mice, which was accompanied by increased inflammation and progressive infiltration of peripheral immune cells. More importantly, treatment with an FDA-approved immunosuppressant, cyclophosphamide (CyP), significantly reduces brain inflammation, improves the neuroanatomical defects and the deficits in LTP and memory deficits, and reverses some of the ASD-like behaviors, notably the social deficits. Collectively, our results reveal the biological basis underlying neurodevelopmental disorders associated with dysfunctional NMD. Moreover, these findings suggest that immunosuppressant drugs, like CyP, may provide a new therapeutic approach for the treatment of patients with mutations in core NMD components.

ORGANISM(S): Mus musculus

PROVIDER: GSE81591 | GEO | 2020/06/29

REPOSITORIES: GEO

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Project description:A major task in analyzing alternative splicing (AS) by RNA-Seq is to explore and quantify the differential representation of various splice classes and the protein-coding potential of the mapped reads. To this end, we have generated a streamlined bioinformatic pipeline available to the scientific community, which maps RNA-Seq reads to a complex combinatorial database of exon-exon junctions for the unique junction discovery, PTC detection and identification of splice isoforms. Hence, we have incorporated a splice isoform inference and PTC detection algorithm, which facilitates a highly accurate mapping and prediction of splice isoform junctions and nonsense-mediated mRNA decay (NMD)-susceptibility. We used this pipeline to investigate the complexity of the transcriptome and global role of AS-NMD in vivo in mammalian cells, by taking advantage of our Upf2 conditional knock-out mouse. Using tissue-specific Cre deleter strains, we have previously demonstrated in vivo that NMD acts to degrade many transcripts that results from AS. Also, ablating UPF2 (a core NMD factor) in the mouse leads to rapid mortality and collapse of most organs tested (Thoren et al., 2010; Weischenfeldt et al., 2008), suggesting an essential function for NMD in AS. To explore the effect of NMD on global splicing and to generate and validate an attractive bioinformatic pipeline for the scientific community to study AS and NMD, we chose to analyze two different mammalian organ systems with distinct phenotypes upon UPF2 ablation to test the robustness and dynamic range of the analysis. In one end of the spectrum, we chose to analyze the liver, wherein removal of UPF2 results in failure in liver metabolism and a high mortality rate (Thoren et al., 2010). To profile a less affected tissue, we chose to analyze bone marrow-derived macrophages (BMMs). These are macrophages that differentiate in vitro and Upf2 deleted BMMs are completely devoid of NMD activity but nevertheless show no morphological or functional phenotype compared to wild-type controls (Weischenfeldt et al., 2008). Thus, we were able to make a direct comparison between these two tissues to demonstrate the potency of our Isoform and PTC detection pipeline described below, which will allow the scientific community to analyze transcriptome data for global AS and NMD-susceptibility. Examination of UPF2 WT vs. KO in two different murine tissues (liver, bone marrow-derived macrophages).

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Upf2-mediated inhibition of nonsense mediated decay causes memory and social deficits by activating the immune response

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