한빛사 논문
Oh‐Chan Kwon1,2,3,†, Jae‐Jin Song1,2,†, Yunseon Yang1,2,3,†, Seong‐Hoon Kim1,2,3, Ji Young Kim1,2,3, Min‐Jong Seok1,2,3, Inhwa Hwang4, Je‐Wook Yu4, Jenisha Karmacharya5, Han‐Joo Maeng5, Jiyoung Kim6, Eek‐hoon Jho6, Seung Yeon Ko1,2,3, Hyeon Son1,2,3, Mi‐Yoon Chang*,1,2 and Sang‐Hun Lee*,1,2,3
1Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seoul, Korea
2Hanyang Biomedical Research Institute, Hanyang University, Seoul, Korea
3Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul
4Korea 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 Korea
5College of Pharmacy, Gachon University, Incheon, Korea
6Department of Life Science, University of Seoul, Seoul, Korea
†These authors contributed equally to this work
*Corresponding author.
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.
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