Amanda Faria Assoni, Erika N. Guerrero, René Wardenaar, Danyllo Oliveira, Petra L. Bakker, Luciana M. Alves, Valdemir M. Carvalho, Oswaldo Keith Okamoto, Mayana Zatz, Floris Foijer
{"title":"在 FUS 相关性肌萎缩侧索硬化症中,IFNγ 通过增强全局蛋白质合成保护运动神经元免受氧化应激的影响","authors":"Amanda Faria Assoni, Erika N. Guerrero, René Wardenaar, Danyllo Oliveira, Petra L. Bakker, Luciana M. Alves, Valdemir M. Carvalho, Oswaldo Keith Okamoto, Mayana Zatz, Floris Foijer","doi":"10.1111/bpa.13206","DOIUrl":null,"url":null,"abstract":"<p>Amyotrophic lateral sclerosis type 6 (ALS6) is a familial subtype of ALS linked to Fused in Sarcoma (FUS) gene mutation. FUS mutations lead to decreased global protein synthesis, but the mechanism that drives this has not been established. Here, we used ALS6 patient-derived induced pluripotent stem cells (hIPSCs) to study the effect of the ALS6 FUS<sup>R521H</sup> mutation on the translation machinery in motor neurons (MNs). We find, in agreement with findings of others, that protein synthesis is decreased in FUS<sup>R521H</sup> MNs. Furthermore, FUS<sup>R521H</sup> MNs are more sensitive to oxidative stress and display reduced expression of TGF-β and mTORC gene pathways when stressed. Finally, we show that IFN<b>γ</b> treatment reduces apoptosis of FUS<sup>R521H</sup> MNs exposed to oxidative stress and partially restores the translation rates in FUS<sup>R521H</sup> MNs. Overall, these findings suggest that a functional IFN<b>γ</b> response is important for FUS-mediated protein synthesis, possibly by FUS nuclear translocation in ALS6.</p>","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":null,"pages":null},"PeriodicalIF":5.8000,"publicationDate":"2023-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bpa.13206","citationCount":"0","resultStr":"{\"title\":\"IFNγ protects motor neurons from oxidative stress via enhanced global protein synthesis in FUS-associated amyotrophic lateral sclerosis\",\"authors\":\"Amanda Faria Assoni, Erika N. Guerrero, René Wardenaar, Danyllo Oliveira, Petra L. Bakker, Luciana M. Alves, Valdemir M. Carvalho, Oswaldo Keith Okamoto, Mayana Zatz, Floris Foijer\",\"doi\":\"10.1111/bpa.13206\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>Amyotrophic lateral sclerosis type 6 (ALS6) is a familial subtype of ALS linked to Fused in Sarcoma (FUS) gene mutation. FUS mutations lead to decreased global protein synthesis, but the mechanism that drives this has not been established. Here, we used ALS6 patient-derived induced pluripotent stem cells (hIPSCs) to study the effect of the ALS6 FUS<sup>R521H</sup> mutation on the translation machinery in motor neurons (MNs). We find, in agreement with findings of others, that protein synthesis is decreased in FUS<sup>R521H</sup> MNs. Furthermore, FUS<sup>R521H</sup> MNs are more sensitive to oxidative stress and display reduced expression of TGF-β and mTORC gene pathways when stressed. Finally, we show that IFN<b>γ</b> treatment reduces apoptosis of FUS<sup>R521H</sup> MNs exposed to oxidative stress and partially restores the translation rates in FUS<sup>R521H</sup> MNs. Overall, these findings suggest that a functional IFN<b>γ</b> response is important for FUS-mediated protein synthesis, possibly by FUS nuclear translocation in ALS6.</p>\",\"PeriodicalId\":9290,\"journal\":{\"name\":\"Brain Pathology\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":5.8000,\"publicationDate\":\"2023-08-15\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bpa.13206\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Brain Pathology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1111/bpa.13206\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CLINICAL NEUROLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Brain Pathology","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1111/bpa.13206","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
IFNγ protects motor neurons from oxidative stress via enhanced global protein synthesis in FUS-associated amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis type 6 (ALS6) is a familial subtype of ALS linked to Fused in Sarcoma (FUS) gene mutation. FUS mutations lead to decreased global protein synthesis, but the mechanism that drives this has not been established. Here, we used ALS6 patient-derived induced pluripotent stem cells (hIPSCs) to study the effect of the ALS6 FUSR521H mutation on the translation machinery in motor neurons (MNs). We find, in agreement with findings of others, that protein synthesis is decreased in FUSR521H MNs. Furthermore, FUSR521H MNs are more sensitive to oxidative stress and display reduced expression of TGF-β and mTORC gene pathways when stressed. Finally, we show that IFNγ treatment reduces apoptosis of FUSR521H MNs exposed to oxidative stress and partially restores the translation rates in FUSR521H MNs. Overall, these findings suggest that a functional IFNγ response is important for FUS-mediated protein synthesis, possibly by FUS nuclear translocation in ALS6.
期刊介绍:
Brain Pathology is the journal of choice for biomedical scientists investigating diseases of the nervous system. The official journal of the International Society of Neuropathology, Brain Pathology is a peer-reviewed quarterly publication that includes original research, review articles and symposia focuses on the pathogenesis of neurological disease.