A Wonderful Journey: The Diverse Roles of Adenosine Deaminase Action on RNA 1 (ADAR1) in Central Nervous System Diseases

CNS Neuroscience & Therapeutics, Год журнала: 2025, Номер 31(1)

Опубликована: Янв. 1, 2025

ABSTRACT Background Adenosine deaminase action on RNA 1 (ADAR1) can convert the adenosine in double‐stranded (dsRNA) molecules into inosine a process known as A‐to‐I editing. ADAR1 regulates gene expression output by interacting with and other proteins; plays important roles development, including growth; is linked to innate immunity, tumors, central nervous system (CNS) diseases. Results In recent years, role of tumors has been widely discussed, but its CNS diseases not reviewed. It worth noting that studies have shown great potential treatment neurodegenerative diseases, mechanisms are still unclear. Therefore, it necessary elaborate Conclusions Here, we focus effects such Aicardi–AicardiGoutières syndrome, Alzheimer's disease, Parkinson's glioblastoma, epilepsy, amyotrophic lateral sclerosis, autism. We also evaluate impact ADAR1‐based strategies these particular development new technologies microRNAs, nanotechnology, editing, stem cell therapy. hope provide directions insights for future editing technology brain science

Язык: Английский

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ADAR1 Regulates Lipid Remodeling through MDM2 to Dictate Ferroptosis Sensitivity

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Янв. 21, 2025

Triple-negative breast cancer (TNBC), lacking expression of estrogen, progesterone, and HER2 receptors, is aggressive lacks targeted treatment options. An RNA editing enzyme, adenosine deaminase acting on 1 (ADAR1), has been shown to play important roles in TNBC tumorigenesis. We posit that ADAR1 functions as a homeostatic factor protecting from internal external pressure, including metabolic stress. tested the hypothesis iron- dependent cell death pathway, ferroptosis, ADAR1-protected vulnerability by showing knockdown sensitizes cells GPX4 inhibitors. By performing single-reaction monitoring-based liquid chromatography coupled mass spectrometry (LC-MS) measure intracellular lipid contents, we showed loss increased abundance polyunsaturated fatty acid phospholipids (PUFA-PL), which peroxidation primary driver ferroptosis. Transcriptomic analyses led discovery proto-oncogene MDM2 contributing remodeling upon loss. A phenotypic drug screen using ferroptosis-focused library was performed identify FDA- approved cobimetinib drug-repurposing candidate synergize with suppress demonstrating regulates fitness through desensitizing aim leverage this inform basic, pre-clinical, clinical studies develop novel therapeutic strategies for TNBC.

Язык: Английский

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ADAR1 haploinsufficiency and sustained viral RdRp dsRNA synthesis synergize to dysregulate RNA editing and cause multi-system interferonopathy

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Янв. 22, 2025

Sensing of viral double-stranded RNA by MDA5 triggers abundant but transient interferon-stimulated gene (ISGs) expression. If dsRNA synthesis is made persistent transgenically expressing a picornaviral RNA-dependent polymerase (RdRp) in mice, lifelong activation and marked, global ISG upregulation result. This confers robust protection from diseases contrast to numerous other chronic hyperactivation states, the mice suffer no autoimmune consequences. Here we find they further confound expectations being resistant strong autoimmunity (lupus) provocation. However, knockout one allele Adar , which itself also well-tolerated, breaks protective state results severe disease that resembles interferonopathies caused gain-of-function mutations. In +/- RdRp transgenic A-to-I editing both dysregulated increased (numbers genes sites). dsRNA-driven, MDA5-wild type model establishes polymerase-sourced can drive interferonopathy pathogenesis illuminates preventing role ADAR1, while ADAR1-intact distinctively uncouples hyperactivity autoinflammatory disease.

Язык: Английский

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Pharmacological evaluation of drug therapies in Aicardi-Goutières syndrome: insights from patient-derived neural stem cells

Frontiers in Pharmacology, Год журнала: 2025, Номер 16

Опубликована: Март 20, 2025

Aicardi-Goutières syndrome (AGS) is a rare genetic disorder classified among type I interferonopathies. Current pharmacological management of AGS symptomatic and supportive, with recent clinical applications JAK inhibitors (JAKi) antiretroviral therapies (RTIs). To investigate the effects these therapies, patient-specific induced pluripotent stem cells (iPSCs) were generated by reprogramming fibroblasts from three patients distinct mutations (AGS1, AGS2, AGS7) differentiated into neural (NSCs). iPSCs NSCs derived commercial BJ healthy donor served as control. The cytotoxic glucocorticoids, thiopurines, (ruxolitinib, baricitinib, tofacitinib, pacritinib), RTIs (abacavir, lamivudine, zidovudine) evaluated using MTT assay. Results showed that glucocorticoids did not compromise NSC viability. Among thioguanine, but mercaptopurine, exhibited cytotoxicity in NSCs. All tested inhibitors, except pacritinib, non-toxic to Interestingly, high concentrations certain tofacitinib) led an unexpected increase cell viability patient-derived compared control, suggesting potential alterations proliferation or stress responses. demonstrated no cytotoxicity, for zidovudine, which selective toxicity AGS2-derived controls. These findings suggest (excluding are likely safe patients, while caution warranted thioguanine pacritinib. Further studies needed explore mechanisms underlying increased at inhibitor sensitivity zidovudine.

Язык: Английский

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Leveraging genetics to understand ADAR1-mediated RNA editing in health and disease

Nature Reviews Genetics, Год журнала: 2025, Номер unknown

Опубликована: Апрель 14, 2025

Язык: Английский

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RNA methylation: A new perspective in osteoarthritis research

Gene, Год журнала: 2025, Номер 959, С. 149518 - 149518

Опубликована: Апрель 18, 2025

Язык: Английский

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MDA5 guards against infection by surveying cellular RNA homeostasis

Опубликована: Апрель 24, 2025

MDA5 is an innate immune RNA sensor that senses infection with a range of viruses and other pathogens. MDA5’s agonists are not well defined. We used single-nucleotide resolution crosslinking immunoprecipitation (iCLIP) to study its ligands. Surprisingly, upon SARS-CoV-2 or encephalomyocarditis virus, bound overwhelmingly cellular RNAs. Many binding sites were intronic proximal Alu elements potentially base-paired structures. Concomitantly, cytoplasmic levels intron-containing unspliced transcripts increased in infected cells displayed enrichment iCLIP peaks. Moreover, overexpression splicing factor abrogated activation. Finally, when depleted viral sequences, extracted from still stimulated MDA5. Taken together, surveys processing fidelity detects infections by sensing perturbations posttranscriptional events such as splicing, establishing paradigm ‘guarding’ for sensors.

Язык: Английский

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Cancer cells restrict immunogenicity of retrotransposon expression via distinct mechanisms

Immunity, Год журнала: 2024, Номер 57(12), С. 2879 - 2894.e11

Опубликована: Ноя. 21, 2024

Язык: Английский

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Identification and characterization of ADAR1 mutations and changes in gene expression in human cancers

Cancer Genetics, Год журнала: 2024, Номер 288-289, С. 82 - 91

Опубликована: Окт. 28, 2024

Язык: Английский

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ADAR1 could be a potential diagnostic target for intrauterine infection patients

Scientific Reports, Год журнала: 2024, Номер 14(1)

Опубликована: Ноя. 27, 2024

Intrauterine infection (IUI) is mainly an ascending in which vaginal and cervical pathogens ascend to the uterus can affect fetus. Until now, there still no effective diagnostic biomarker for IUI, such as chorioamnionitis (CAM) funisitis (FUN). Deoxyribonucleic acid (DNA)/Ribonucleic (RNA) editing molecules apolipoprotein-B mRNA-editing complex (APOBEC) 3 families Adenosine deaminase family acting on RNA (ADAR)1 were examined chorioamniotic membranes umbilical cord of 83 patient samples. Furthermore, Ureaplasma parvum induced ADAR1 was investigated human HTR-8/SVneo EVT cell line. had a significantly higher area under curve (AUC) (0.721 0.745) than other APOBEC3s or cytokines CAM FUN patients. In vitro, ureaplasma demonstrated activate (p = 0.025) reduce RIG-I, IRF3, IFN- $$\:{\upalpha\:}$$ , IFN-β expression line 0.005, p 0.010, < 0.001, 0.018, respectively). High strongly associated with patients (multivariate analyses; 0.035 0.002). could be potential target

Язык: Английский

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