Targeting EGLN2/PHD1 protects motor neurons and normalizes the astrocytic interferon response

IF 7.5 1区生物学 Q1 CELL BIOLOGY Cell reports Pub Date : 2024-09-09 DOI:10.1016/j.celrep.2024.114719

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":"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":"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.","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}

引用次数: 0

Abstract

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.

Abstract Image

查看原文

微信好友朋友圈 QQ好友复制链接

本刊更多论文

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

神经炎症和能量代谢失调与肌萎缩侧索硬化症（ALS）的运动神经元变性有关。egl-9家族缺氧诱导因子（EGLN）酶又称脯氨酰羟化酶域（PHD）酶，是调节细胞炎症和新陈代谢的代谢传感器。我们利用寡核苷酸和遗传学方法证明，在两种斑马鱼模型和一种肌萎缩性脊髓侧索硬化症小鼠模型中，下调 Egln2 可以保护运动神经元并减轻肌萎缩性脊髓侧索硬化症的表型。小鼠脊髓的单核 RNA 测序显示，EGLN2 的缺失会诱导星形胶质细胞特异性下调干扰素刺激基因，这种下调是通过干扰素基因刺激器（STING）蛋白介导的。此外，我们还发现，在患者诱导多能干细胞（iPSC）衍生的星形胶质细胞中，基因缺失EGLN2可恢复这种干扰素反应，从而证实了EGLN2与星形胶质细胞干扰素信号转导之间的联系。总之，我们确定了 EGLN2 作为运动神经元保护靶点，可在体内和患者衍生细胞中使星形胶质细胞干扰素依赖性炎症轴正常化。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文去求助

来源期刊

Cell reports CELL BIOLOGY-

CiteScore

13.80

自引率

1.10%

发文量

1305

审稿时长

77 days

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. The Cell Reports Portfolio includes gold open-access journals that cover life, medical, and physical sciences, and its mission is to make cutting-edge research and methodologies available to a wide readership. The journal's professional in-house editors work closely with authors, reviewers, and the scientific advisory board, which consists of current and future leaders in their respective fields. The advisory board guides the scope, content, and quality of the journal, but editorial decisions are independently made by the in-house scientific editors of Cell Reports.