SGK1 inhibition in glia ameliorates pathologies and symptoms in Parkinson disease animal models
Abstract Astrocytes and microglia are brain‐resident glia that can establish harmful inflammatory environments in disease contexts and thereby contribute to the progression of neuronal loss in neurodegenerative disorders. Correcting the diseased properties of glia is therefore an appealing strategy...
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Online Access: | https://doi.org/10.15252/emmm.202013076 |
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doaj-80e6140a7a3c4c5090b8e18df7c579b72021-08-02T19:37:50ZengWileyEMBO Molecular Medicine1757-46761757-46842021-04-01134n/an/a10.15252/emmm.202013076SGK1 inhibition in glia ameliorates pathologies and symptoms in Parkinson disease animal modelsOh‐Chan Kwon0Jae‐Jin Song1Yunseon Yang2Seong‐Hoon Kim3Ji Young Kim4Min‐Jong Seok5Inhwa Hwang6Je‐Wook Yu7Jenisha Karmacharya8Han‐Joo Maeng9Jiyoung Kim10Eek‐hoon Jho11Seung Yeon Ko12Hyeon Son13Mi‐Yoon Chang14Sang‐Hun Lee15Department of Biochemistry and Molecular Biology College of Medicine Hanyang University Seoul KoreaDepartment of Biochemistry and Molecular Biology College of Medicine Hanyang University Seoul KoreaDepartment of Biochemistry and Molecular Biology College of Medicine Hanyang University Seoul KoreaDepartment of Biochemistry and Molecular Biology College of Medicine Hanyang University Seoul KoreaDepartment of Biochemistry and Molecular Biology College of Medicine Hanyang University Seoul KoreaDepartment of Biochemistry and Molecular Biology College of Medicine Hanyang University Seoul KoreaKorea Department of Microbiology and Immunology Institute for Immunology and Immunological Diseases Brain Korea 21 PLUS Project for Medical Science Yonsei University College of Medicine Seoul South KoreaKorea Department of Microbiology and Immunology Institute for Immunology and Immunological Diseases Brain Korea 21 PLUS Project for Medical Science Yonsei University College of Medicine Seoul South KoreaCollege of Pharmacy Gachon University Incheon KoreaCollege of Pharmacy Gachon University Incheon KoreaDepartment of Life Science University of Seoul Seoul KoreaDepartment of Life Science University of Seoul Seoul KoreaDepartment of Biochemistry and Molecular Biology College of Medicine Hanyang University Seoul KoreaDepartment of Biochemistry and Molecular Biology College of Medicine Hanyang University Seoul KoreaDepartment of Biochemistry and Molecular Biology College of Medicine Hanyang University Seoul KoreaDepartment of Biochemistry and Molecular Biology College of Medicine Hanyang University Seoul KoreaAbstract Astrocytes and microglia are brain‐resident glia that can establish harmful inflammatory environments in disease contexts and thereby contribute to the progression of neuronal loss in neurodegenerative disorders. Correcting the diseased properties of glia is therefore an appealing strategy for treating brain diseases. Previous studies have shown that serum/ glucocorticoid related kinase 1 (SGK1) is upregulated in the brains of patients with various neurodegenerative disorders, suggesting its involvement in the pathogenesis of those diseases. In this study, we show that inhibiting glial SGK1 corrects the pro‐inflammatory properties of glia by suppressing the intracellular NFκB‐, NLRP3‐inflammasome‐, and CGAS‐STING‐mediated inflammatory pathways. Furthermore, SGK1 inhibition potentiated glial activity to scavenge glutamate toxicity and prevented glial cell senescence and mitochondrial damage, which have recently been reported as critical pathologic features of and therapeutic targets in Parkinson disease (PD) and Alzheimer disease (AD). Along with those anti‐inflammatory/neurotrophic functions, silencing and pharmacological inhibition of SGK1 protected midbrain dopamine neurons from degeneration and cured pathologic synuclein alpha (SNCA) aggregation and PD‐associated behavioral deficits in multiple in vitro and in vivo PD models. Collectively, these findings suggest that SGK1 inhibition could be a useful strategy for treating PD and other neurodegenerative disorders that share the common pathology of glia‐mediated neuroinflammation.https://doi.org/10.15252/emmm.202013076glianeuroinflammationParkinson’s diseaseserum/glucocorticoid related kinase 1synuclein alpha |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Oh‐Chan Kwon Jae‐Jin Song Yunseon Yang Seong‐Hoon Kim Ji Young Kim Min‐Jong Seok Inhwa Hwang Je‐Wook Yu Jenisha Karmacharya Han‐Joo Maeng Jiyoung Kim Eek‐hoon Jho Seung Yeon Ko Hyeon Son Mi‐Yoon Chang Sang‐Hun Lee |
spellingShingle |
Oh‐Chan Kwon Jae‐Jin Song Yunseon Yang Seong‐Hoon Kim Ji Young Kim Min‐Jong Seok Inhwa Hwang Je‐Wook Yu Jenisha Karmacharya Han‐Joo Maeng Jiyoung Kim Eek‐hoon Jho Seung Yeon Ko Hyeon Son Mi‐Yoon Chang Sang‐Hun Lee SGK1 inhibition in glia ameliorates pathologies and symptoms in Parkinson disease animal models EMBO Molecular Medicine glia neuroinflammation Parkinson’s disease serum/glucocorticoid related kinase 1 synuclein alpha |
author_facet |
Oh‐Chan Kwon Jae‐Jin Song Yunseon Yang Seong‐Hoon Kim Ji Young Kim Min‐Jong Seok Inhwa Hwang Je‐Wook Yu Jenisha Karmacharya Han‐Joo Maeng Jiyoung Kim Eek‐hoon Jho Seung Yeon Ko Hyeon Son Mi‐Yoon Chang Sang‐Hun Lee |
author_sort |
Oh‐Chan Kwon |
title |
SGK1 inhibition in glia ameliorates pathologies and symptoms in Parkinson disease animal models |
title_short |
SGK1 inhibition in glia ameliorates pathologies and symptoms in Parkinson disease animal models |
title_full |
SGK1 inhibition in glia ameliorates pathologies and symptoms in Parkinson disease animal models |
title_fullStr |
SGK1 inhibition in glia ameliorates pathologies and symptoms in Parkinson disease animal models |
title_full_unstemmed |
SGK1 inhibition in glia ameliorates pathologies and symptoms in Parkinson disease animal models |
title_sort |
sgk1 inhibition in glia ameliorates pathologies and symptoms in parkinson disease animal models |
publisher |
Wiley |
series |
EMBO Molecular Medicine |
issn |
1757-4676 1757-4684 |
publishDate |
2021-04-01 |
description |
Abstract Astrocytes and microglia are brain‐resident glia that can establish harmful inflammatory environments in disease contexts and thereby contribute to the progression of neuronal loss in neurodegenerative disorders. Correcting the diseased properties of glia is therefore an appealing strategy for treating brain diseases. Previous studies have shown that serum/ glucocorticoid related kinase 1 (SGK1) is upregulated in the brains of patients with various neurodegenerative disorders, suggesting its involvement in the pathogenesis of those diseases. In this study, we show that inhibiting glial SGK1 corrects the pro‐inflammatory properties of glia by suppressing the intracellular NFκB‐, NLRP3‐inflammasome‐, and CGAS‐STING‐mediated inflammatory pathways. Furthermore, SGK1 inhibition potentiated glial activity to scavenge glutamate toxicity and prevented glial cell senescence and mitochondrial damage, which have recently been reported as critical pathologic features of and therapeutic targets in Parkinson disease (PD) and Alzheimer disease (AD). Along with those anti‐inflammatory/neurotrophic functions, silencing and pharmacological inhibition of SGK1 protected midbrain dopamine neurons from degeneration and cured pathologic synuclein alpha (SNCA) aggregation and PD‐associated behavioral deficits in multiple in vitro and in vivo PD models. Collectively, these findings suggest that SGK1 inhibition could be a useful strategy for treating PD and other neurodegenerative disorders that share the common pathology of glia‐mediated neuroinflammation. |
topic |
glia neuroinflammation Parkinson’s disease serum/glucocorticoid related kinase 1 synuclein alpha |
url |
https://doi.org/10.15252/emmm.202013076 |
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