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A zebrafish model of Ifih1-driven Aicardi-Goutières syndrome reproduces the interferon signature and the exacerbated inflammation of patients

ABSTRACT: A zebrafish model of Ifih1-driven Aicardi-Goutières syndrome reproduces the interferon signature and the exacerbated inflammation of patients

PROVIDER: PRJNA1022095 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR26212801_1.fastq.gz	Fastqsanger.gz
	SRR26212801_2.fastq.gz	Fastqsanger.gz
	SRR26212802_1.fastq.gz	Fastqsanger.gz
	SRR26212802_2.fastq.gz	Fastqsanger.gz
	SRR26212803_1.fastq.gz	Fastqsanger.gz

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Project description:Aicardi-Goutières syndrome (AGS) is a genetically heterogeneous encephalopathy whose pathology is linked to an abnormal type I interferon response induced by self-derived nucleic acids. Data indicate that endogenous retroelements represent one source of interferon-stimulatory self-nucleic acid. No effective therapies are available for this disorder. In this pilot study involving patients with AGS due to mutations in TREX1, RNASEH2A, RNASEH2B or SAMHD1 three nucleoside analogue reverse transcriptase inhibitors (RTIs) were administered over 12 months. Transcription profiling was done by RNA-seq.

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A zebrafish model of Ifih1-driven Aicardi-Goutières syndrome reproduces the interferon signature and the exacerbated inflammation of patients

Project description:Type I Interferonopathies are a heterogenic group of rare diseases associated with an increase of type I interferon (IFN). The main challenge for the study of Type I interferonopathies is the lack of a well-founded animal model in which better characterize the phenotype as well as to perform fast and large drug screenings to offer the best treatment options. In this study, we report the development of a transgenic zebrafish model of Type I interferonopathy overexpressing ifih1 carrying the mutation p.Arg742His (Tg(ifih1_mut)), corresponding to the human mutation p.Arg779His. RNA sequence analysis from Tg(ifih1_mut) larvae revealed a systemic inflammation and IFN signature upon a suboptimal poly I:C induction compared with wild type larvae, confirming the phenotype observed in patients suffering from Type I interferonopathies. More interestingly, the phenotype was manifested in the zebrafish inflammation and Type I IFN reporters nfkb:eGFP and isg15:eGFP, respectively, making this zebrafish model suitable for future high throughput chemical screening (HTS). Using the unique advantages of the zebrafish model for gene editing we have generated Tg(ifih1_mut) knocked down for mavs and ikbke, that completely abrogated the Poly I:C induction and activation of the GFP of the reporters. Finally, we used an FDA approved drug, Baricitinib (Jak1/Jak2 inhibitor), which was able to reduce the inflammation and the ISGs expression. Our results demonstrate the potential of this model to further understand AGS pathological mechanisms and to identify novel therapeutic drugs by HTS.

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DNA damage contributes to neurotoxic inflammation in Aicardi-Goutières Syndrome astrocytes [RNA-Seq]

Project description:We generated iPS cells knock out (KO) for two Aicardi Goutières syndrome genes, TREX1 and RNASEH2b to model the disease in a human neurological context. Their transcriptomes were analyzed at several differentiation stages: iPSC-derived Neural Stem Cells, iPSC-derived proinflammatory astrocytes and iPSC-derived neurons. We then evaluated when and to which extent the AGS-related transcriptional alterations arised in all KO and WT cells.

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DNA damage contributes to neurotoxic inflammation in Aicardi-Goutières Syndrome astrocytes

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A zebrafish model of Ifih1-driven Aicardi-Goutieres syndrome reproduces the interferon signature and the exacerbated inflammation of patients.

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