Characterization of a mutant samhd1 zebrafish model implicates dysregulation of cholesterol biosynthesis in Aicardi-Goutières syndrome
Aicardi-Goutières syndrome (AGS1-9) is a genetically determined encephalopathy that falls under the type I interferonopathy disease class, characterized by excessive type I interferon (IFN-I) activity, coupled with upregulation of IFN-stimulated genes (ISGs), which can be explained by the vital role...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-03-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1100967/full |
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| author | Sarah E. Withers Sarah E. Withers Charlie F. Rowlands Charlie F. Rowlands Victor S. Tapia Victor S. Tapia Frances Hedley Frances Hedley Ioana-Emilia Mosneag Ioana-Emilia Mosneag Siobhan Crilly Siobhan Crilly Gillian I. Rice Gillian I. Rice Andrew P. Badrock Andrew Hayes Stuart M. Allan Stuart M. Allan Stuart M. Allan Tracy A. Briggs Tracy A. Briggs Tracy A. Briggs Paul R. Kasher Paul R. Kasher Paul R. Kasher |
| author_facet | Sarah E. Withers Sarah E. Withers Charlie F. Rowlands Charlie F. Rowlands Victor S. Tapia Victor S. Tapia Frances Hedley Frances Hedley Ioana-Emilia Mosneag Ioana-Emilia Mosneag Siobhan Crilly Siobhan Crilly Gillian I. Rice Gillian I. Rice Andrew P. Badrock Andrew Hayes Stuart M. Allan Stuart M. Allan Stuart M. Allan Tracy A. Briggs Tracy A. Briggs Tracy A. Briggs Paul R. Kasher Paul R. Kasher Paul R. Kasher |
| author_sort | Sarah E. Withers |
| collection | DOAJ |
| description | Aicardi-Goutières syndrome (AGS1-9) is a genetically determined encephalopathy that falls under the type I interferonopathy disease class, characterized by excessive type I interferon (IFN-I) activity, coupled with upregulation of IFN-stimulated genes (ISGs), which can be explained by the vital role these proteins play in self-non-self-discrimination. To date, few mouse models fully replicate the vast clinical phenotypes observed in AGS patients. Therefore, we investigated the use of zebrafish as an alternative species for generating a clinically relevant model of AGS. Using CRISPR-cas9 technology, we generated a stable mutant zebrafish line recapitulating AGS5, which arises from recessive mutations in SAMHD1. The resulting homozygous mutant zebrafish larvae possess a number of neurological phenotypes, exemplified by variable, but increased expression of several ISGs in the head region, a significant increase in brain cell death, microcephaly and locomotion deficits. A link between IFN-I signaling and cholesterol biosynthesis has been highlighted by others, but not previously implicated in the type I interferonopathies. Through assessment of neurovascular integrity and qPCR analysis we identified a significant dysregulation of cholesterol biosynthesis in the zebrafish model. Furthermore, dysregulation of cholesterol biosynthesis gene expression was also observed through RNA sequencing analysis of AGS patient whole blood. From this novel finding, we hypothesize that cholesterol dysregulation may play a role in AGS disease pathophysiology. Further experimentation will lend critical insight into the molecular pathophysiology of AGS and the potential links involving aberrant type I IFN signaling and cholesterol dysregulation. |
| first_indexed | 2024-04-10T05:42:55Z |
| format | Article |
| id | doaj.art-21996985323c40e7b3c222331fcef159 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-10T05:42:55Z |
| publishDate | 2023-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-21996985323c40e7b3c222331fcef1592023-03-06T06:00:46ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-03-011410.3389/fimmu.2023.11009671100967Characterization of a mutant samhd1 zebrafish model implicates dysregulation of cholesterol biosynthesis in Aicardi-Goutières syndromeSarah E. Withers0Sarah E. Withers1Charlie F. Rowlands2Charlie F. Rowlands3Victor S. Tapia4Victor S. Tapia5Frances Hedley6Frances Hedley7Ioana-Emilia Mosneag8Ioana-Emilia Mosneag9Siobhan Crilly10Siobhan Crilly11Gillian I. Rice12Gillian I. Rice13Andrew P. Badrock14Andrew Hayes15Stuart M. Allan16Stuart M. Allan17Stuart M. Allan18Tracy A. Briggs19Tracy A. Briggs20Tracy A. Briggs21Paul R. Kasher22Paul R. Kasher23Paul R. Kasher24Division of Neuroscience, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Manchester, United KingdomGeoffrey Jefferson Brain Research Centre, The Manchester Academic Health Science Centre, Northern Care Alliance National Health Service (NHS) Foundation Trust, The University of Manchester, Manchester, United KingdomDivision of Evolution, Infection and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United KingdomManchester Centre for Genomic Medicine, St. Mary’s Hospital, Manchester University National Health Service (NHS) Foundation Trust, Manchester Academic Health Science Centre, Manchester, United KingdomDivision of Neuroscience, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Manchester, United KingdomGeoffrey Jefferson Brain Research Centre, The Manchester Academic Health Science Centre, Northern Care Alliance National Health Service (NHS) Foundation Trust, The University of Manchester, Manchester, United KingdomDivision of Neuroscience, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Manchester, United KingdomGeoffrey Jefferson Brain Research Centre, The Manchester Academic Health Science Centre, Northern Care Alliance National Health Service (NHS) Foundation Trust, The University of Manchester, Manchester, United KingdomDivision of Neuroscience, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Manchester, United KingdomGeoffrey Jefferson Brain Research Centre, The Manchester Academic Health Science Centre, Northern Care Alliance National Health Service (NHS) Foundation Trust, The University of Manchester, Manchester, United KingdomDivision of Neuroscience, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Manchester, United KingdomGeoffrey Jefferson Brain Research Centre, The Manchester Academic Health Science Centre, Northern Care Alliance National Health Service (NHS) Foundation Trust, The University of Manchester, Manchester, United KingdomDivision of Evolution, Infection and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United KingdomManchester Centre for Genomic Medicine, St. Mary’s Hospital, Manchester University National Health Service (NHS) Foundation Trust, Manchester Academic Health Science Centre, Manchester, United KingdomMedical Research Council (MRC) Human Genetics Unit, University of Edinburgh, Edinburgh, United KingdomGenomic Technologies Core Facility, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United KingdomDivision of Neuroscience, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Manchester, United KingdomGeoffrey Jefferson Brain Research Centre, The Manchester Academic Health Science Centre, Northern Care Alliance National Health Service (NHS) Foundation Trust, The University of Manchester, Manchester, United KingdomLydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, United KingdomDivision of Evolution, Infection and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United KingdomManchester Centre for Genomic Medicine, St. Mary’s Hospital, Manchester University National Health Service (NHS) Foundation Trust, Manchester Academic Health Science Centre, Manchester, United KingdomLydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, United KingdomDivision of Neuroscience, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Manchester, United KingdomGeoffrey Jefferson Brain Research Centre, The Manchester Academic Health Science Centre, Northern Care Alliance National Health Service (NHS) Foundation Trust, The University of Manchester, Manchester, United KingdomLydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, United KingdomAicardi-Goutières syndrome (AGS1-9) is a genetically determined encephalopathy that falls under the type I interferonopathy disease class, characterized by excessive type I interferon (IFN-I) activity, coupled with upregulation of IFN-stimulated genes (ISGs), which can be explained by the vital role these proteins play in self-non-self-discrimination. To date, few mouse models fully replicate the vast clinical phenotypes observed in AGS patients. Therefore, we investigated the use of zebrafish as an alternative species for generating a clinically relevant model of AGS. Using CRISPR-cas9 technology, we generated a stable mutant zebrafish line recapitulating AGS5, which arises from recessive mutations in SAMHD1. The resulting homozygous mutant zebrafish larvae possess a number of neurological phenotypes, exemplified by variable, but increased expression of several ISGs in the head region, a significant increase in brain cell death, microcephaly and locomotion deficits. A link between IFN-I signaling and cholesterol biosynthesis has been highlighted by others, but not previously implicated in the type I interferonopathies. Through assessment of neurovascular integrity and qPCR analysis we identified a significant dysregulation of cholesterol biosynthesis in the zebrafish model. Furthermore, dysregulation of cholesterol biosynthesis gene expression was also observed through RNA sequencing analysis of AGS patient whole blood. From this novel finding, we hypothesize that cholesterol dysregulation may play a role in AGS disease pathophysiology. Further experimentation will lend critical insight into the molecular pathophysiology of AGS and the potential links involving aberrant type I IFN signaling and cholesterol dysregulation.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1100967/fullAicardi Goutières syndromecholesterolzebrafish disease modelstype I interferonopathySAMHD1 |
| spellingShingle | Sarah E. Withers Sarah E. Withers Charlie F. Rowlands Charlie F. Rowlands Victor S. Tapia Victor S. Tapia Frances Hedley Frances Hedley Ioana-Emilia Mosneag Ioana-Emilia Mosneag Siobhan Crilly Siobhan Crilly Gillian I. Rice Gillian I. Rice Andrew P. Badrock Andrew Hayes Stuart M. Allan Stuart M. Allan Stuart M. Allan Tracy A. Briggs Tracy A. Briggs Tracy A. Briggs Paul R. Kasher Paul R. Kasher Paul R. Kasher Characterization of a mutant samhd1 zebrafish model implicates dysregulation of cholesterol biosynthesis in Aicardi-Goutières syndrome Frontiers in Immunology Aicardi Goutières syndrome cholesterol zebrafish disease models type I interferonopathy SAMHD1 |
| title | Characterization of a mutant samhd1 zebrafish model implicates dysregulation of cholesterol biosynthesis in Aicardi-Goutières syndrome |
| title_full | Characterization of a mutant samhd1 zebrafish model implicates dysregulation of cholesterol biosynthesis in Aicardi-Goutières syndrome |
| title_fullStr | Characterization of a mutant samhd1 zebrafish model implicates dysregulation of cholesterol biosynthesis in Aicardi-Goutières syndrome |
| title_full_unstemmed | Characterization of a mutant samhd1 zebrafish model implicates dysregulation of cholesterol biosynthesis in Aicardi-Goutières syndrome |
| title_short | Characterization of a mutant samhd1 zebrafish model implicates dysregulation of cholesterol biosynthesis in Aicardi-Goutières syndrome |
| title_sort | characterization of a mutant samhd1 zebrafish model implicates dysregulation of cholesterol biosynthesis in aicardi goutieres syndrome |
| topic | Aicardi Goutières syndrome cholesterol zebrafish disease models type I interferonopathy SAMHD1 |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1100967/full |
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