Project description:Alternative splicing (AS) is particularly relevant to cancer progression and apoptosis. Although previous studies have shown that the apurinic-apyrimidinic endonuclease-1 (APEX1) is involved in tumor progression, it is unclear whether APEX1 can regulate AS on cell proliferation and apoptosis of Non-small-cell lung cancer (NSCLC). We performed a comprehensive analysis of the APEX1 expression in 517 lung NSCLC samples from the TCGA (Cancer Genome Atlas) database, and selected two sets of cancer samples with differentially expression APEX1 to analyze potential APEX1-regulated alternative splicing events (ASEs). Functional analysis of the APEX1 in A549 cells were performed in vitro. The APEX1 was overexpression in A549 cell by gene transfection. We identified AS targets regulated by APEX1, analyzed the GO biological process and KEGG functional pathways, and validated APEX1-regulated ASEs detected by RNA-seq and RT-PCR in A549 cells, then in clinical NSCLC samples these results were verified. The expression of the APEX1 was up-regulated in NSCLC samples, and overexpression of the APEX1 resulted in cell proliferation reduction and apoptosis induction. AS of many genes regulated by the APEX1 were enrich in cancer-related functional pathways. Results from A549 cell model and clinical samples showed that the MAPK signaling pathway, the Wnt signaling pathway were shared among the top ten enriched GO processes and KEGG functional pathways. According to our research, the validated AS events regulated by APEX1 mostly located in genes encoding transcription regulation factor in various signaling pathways, including the AXIN1 (axis inhibition protein 1), GCNT2 (N-acetyl glucosaminyl transferase 2), SMAD3 (SMAD Family Member 3), CTBP2 (C-Terminal Binding Protein 2). In this study, we successfully applied RNA-seq technology to demonstrate APEX1 regulation of AS. Our results underline that APEX1 was efficiently up-regulated in NSCLC samples, while overexpression of the APEX1 in A549 cells resulted in proliferation reduction and apoptosis induction. We confirm that the APEX1 regulates the AS of many genes which involved in cancer proliferation and apoptosis functional pathways, such as the MAPK signaling pathway and the Wnt signaling pathway, leading to mediate lung cancer progression. We found that high expression of the APEX1 in NSCLC is an independent prognostic factor related to tumor progression. Therefore, the APEX1 can serve as a molecular marker or therapeutic target for NSCLC treatment.

Project description:Attention deficit hyperactivity disorder (ADHD) is a childhood onset neurodevelopmental disorder with a large genetic risk component. It affects around 5% of children and 2.5% of adults and is associated with a range of severe outcomes. Here we identify three genes (MAP1A, ANO8, ANK2, P < 3.07e-6) implicated in ADHD by rare coding variants from exome sequencing of 8,895 individuals with ADHD and 53,780 controls. Rare deleterious variants in the three genes confer substantial risk for ADHD (odds ratios 5.55 - 15.13) and explain 5.2% of the overall rare variant heritability of ADHD, which was estimated to 2.5%. Protein-protein interaction networks of the three identified genes were enriched for rare variant risk of other neurodevelopmental disorders, and enrichment analyses pointed towards involvement of the networks in cytoskeleton organization, synapse function, and RNA processing. The top associated rare variant risk genes showed an increased mean expression across both pre- and postnatal brain developmental stages, with enrichment in several neuronal cell types including GABAergic and dopaminergic neurons, as well as among genes expressed in axons and in ion channel diseases. Rare protein-truncating variants were associated with lower socioeconomic status and lower education in individuals with ADHD, both before and after excluding individuals with co-occurring intellectual disability (ID). In line with this we identified a decrease in 2.25 intelligence quotient (IQ) points per rare deleterious variant in a German sample of adults with ADHD (N = 962). Individuals with both ADHD and ID showed increased load of rare variant risk overall, while individuals with other psychiatric comorbidities demonstrated increased load only for specific neurodevelopmental disorder gene sets. This suggests that psychiatric comorbidity (other than ID) in ADHD primarily is driven by rare variants in specific genes, rather than a general increased load across constrained genes.

Project description:Mutations in the gene encoding Cu-Zn superoxide dismutase 1 (SOD1) cause a subset of familial amyotrophic lateral sclerosis (fALS) cases. A shared effect of these mutations is that SOD1, which is normally a stable dimer, dissociates into toxic monomers that seed toxic aggregates. Considerable research effort has been devoted to developing compounds that stabilize the dimer of fALS SOD1 variants, but unfortunately, this has not yet resulted in a treatment. We hypothesized that cyclic thiosulfinate cross-linkers, which selectively target a rare, two cysteine-containing motif, can stabilize fALS-causing SOD1 variants in vivo. We created a library of chemically diverse cyclic thiosulfinates and determined structure-cross-linking-activity relationships. A pre-lead compound, “S-XL6,” was selected based upon its cross-linking rate and drug-like properties. Co-crystallographic structure clearly establishes the binding of S-XL6 at Cys 111 bridging the monomers and stabilizing the SOD1 dimer. Biophysical studies reveal that the degree of stabilization afforded by S-XL6 (up to 24 °C) is unprecedented for fALS, and to our knowledge, for any protein target of any kinetic stabilizer. Gene silencing and protein degrading therapeutic approaches require careful dose titration to balance the benefit of diminished fALS SOD1 expression with the toxic loss-of enzymatic function. We show that S-XL6 does not share this liability because it rescues the activity of fALS SOD1 variants. No pharmacological agent has been proven to bind to SOD1 in vivo. Here, using a fALS mouse model, we demonstrate oral bioavailability; rapid engagement of SOD1G93A by S-XL6 that increases SOD1G93A’s in vivo half-life; and that S-XL6 crosses the blood-brain barrier. S-XL6 demonstrated a degree of selectivity by avoiding off-target binding to plasma proteins. Taken together, our results indicate that cyclic thiosulfinate-mediated SOD1 stabilization should receive further attention as a potential therapeutic approach for fALS.

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APEX1 in fALS

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