Christine Germeys, Tijs Vandoorne, Kristofer Davie, Suresh Poovathingal, Kara Heeren, Wendy Vermeire, FatemehArefeh Nami, Matthieu Moisse, Annelies Quaegebeur, Annerieke Sierksma, Laura Rué, Adrià Sicart, Caroline Eykens, Lenja De Cock, Bart De Strooper, Peter Carmeliet, Philip Van Damme, Katrien De Bock, Ludo Van Den Bosch
{"title":"靶向 EGLN2/PHD1 可保护运动神经元并使星形胶质细胞的干扰素反应正常化","authors":"Christine Germeys, Tijs Vandoorne, Kristofer Davie, Suresh Poovathingal, Kara Heeren, Wendy Vermeire, FatemehArefeh Nami, Matthieu Moisse, Annelies Quaegebeur, Annerieke Sierksma, Laura Rué, Adrià Sicart, Caroline Eykens, Lenja De Cock, Bart De Strooper, Peter Carmeliet, Philip Van Damme, Katrien De Bock, Ludo Van Den Bosch","doi":"10.1016/j.celrep.2024.114719","DOIUrl":null,"url":null,"abstract":"<p>Neuroinflammation and dysregulated energy metabolism are linked to motor neuron degeneration in amyotrophic lateral sclerosis (ALS). The egl-9 family hypoxia-inducible factor (EGLN) enzymes, also known as prolyl hydroxylase domain (PHD) enzymes, are metabolic sensors regulating cellular inflammation and metabolism. Using an oligonucleotide-based and a genetic approach, we showed that the downregulation of <em>Egln2</em> protected motor neurons and mitigated the ALS phenotype in two zebrafish models and a mouse model of ALS. Single-nucleus RNA sequencing of the murine spinal cord revealed that the loss of EGLN2 induced an astrocyte-specific downregulation of interferon-stimulated genes, mediated via the stimulator of interferon genes (STING) protein. In addition, we found that the genetic deletion of <em>EGLN2</em> restored this interferon response in patient induced pluripotent stem cell (iPSC)-derived astrocytes, confirming the link between EGLN2 and astrocytic interferon signaling. In conclusion, we identified EGLN2 as a motor neuron protective target normalizing the astrocytic interferon-dependent inflammatory axis <em>in vivo</em>, as well as in patient-derived cells.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":null,"pages":null},"PeriodicalIF":7.5000,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Targeting EGLN2/PHD1 protects motor neurons and normalizes the astrocytic interferon response\",\"authors\":\"Christine Germeys, Tijs Vandoorne, Kristofer Davie, Suresh Poovathingal, Kara Heeren, Wendy Vermeire, FatemehArefeh Nami, Matthieu Moisse, Annelies Quaegebeur, Annerieke Sierksma, Laura Rué, Adrià Sicart, Caroline Eykens, Lenja De Cock, Bart De Strooper, Peter Carmeliet, Philip Van Damme, Katrien De Bock, Ludo Van Den Bosch\",\"doi\":\"10.1016/j.celrep.2024.114719\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>Neuroinflammation and dysregulated energy metabolism are linked to motor neuron degeneration in amyotrophic lateral sclerosis (ALS). The egl-9 family hypoxia-inducible factor (EGLN) enzymes, also known as prolyl hydroxylase domain (PHD) enzymes, are metabolic sensors regulating cellular inflammation and metabolism. Using an oligonucleotide-based and a genetic approach, we showed that the downregulation of <em>Egln2</em> protected motor neurons and mitigated the ALS phenotype in two zebrafish models and a mouse model of ALS. Single-nucleus RNA sequencing of the murine spinal cord revealed that the loss of EGLN2 induced an astrocyte-specific downregulation of interferon-stimulated genes, mediated via the stimulator of interferon genes (STING) protein. In addition, we found that the genetic deletion of <em>EGLN2</em> restored this interferon response in patient induced pluripotent stem cell (iPSC)-derived astrocytes, confirming the link between EGLN2 and astrocytic interferon signaling. In conclusion, we identified EGLN2 as a motor neuron protective target normalizing the astrocytic interferon-dependent inflammatory axis <em>in vivo</em>, as well as in patient-derived cells.</p>\",\"PeriodicalId\":9798,\"journal\":{\"name\":\"Cell reports\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":7.5000,\"publicationDate\":\"2024-09-09\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cell reports\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.1016/j.celrep.2024.114719\",\"RegionNum\":1,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell reports","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1016/j.celrep.2024.114719","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
Targeting EGLN2/PHD1 protects motor neurons and normalizes the astrocytic interferon response
Neuroinflammation and dysregulated energy metabolism are linked to motor neuron degeneration in amyotrophic lateral sclerosis (ALS). The egl-9 family hypoxia-inducible factor (EGLN) enzymes, also known as prolyl hydroxylase domain (PHD) enzymes, are metabolic sensors regulating cellular inflammation and metabolism. Using an oligonucleotide-based and a genetic approach, we showed that the downregulation of Egln2 protected motor neurons and mitigated the ALS phenotype in two zebrafish models and a mouse model of ALS. Single-nucleus RNA sequencing of the murine spinal cord revealed that the loss of EGLN2 induced an astrocyte-specific downregulation of interferon-stimulated genes, mediated via the stimulator of interferon genes (STING) protein. In addition, we found that the genetic deletion of EGLN2 restored this interferon response in patient induced pluripotent stem cell (iPSC)-derived astrocytes, confirming the link between EGLN2 and astrocytic interferon signaling. In conclusion, we identified EGLN2 as a motor neuron protective target normalizing the astrocytic interferon-dependent inflammatory axis in vivo, as well as in patient-derived cells.
期刊介绍:
Cell Reports publishes high-quality research across the life sciences and focuses on new biological insight as its primary criterion for publication. The journal offers three primary article types: Reports, which are shorter single-point articles, research articles, which are longer and provide deeper mechanistic insights, and resources, which highlight significant technical advances or major informational datasets that contribute to biological advances. Reviews covering recent literature in emerging and active fields are also accepted.
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