title: Induction of COX-2-PGE2 synthesis by activation of the MAPK/ERK pathway contributes to neuronal death triggered by TDP-43-depleted microglia.
abstract: Neuroinflammation is a striking hallmark of amyotrophic lateral sclerosis (ALS) and other neurodegenerative disorders. Previous studies have shown the contribution of glial cells such as astrocytes in TDP-43-linked ALS. However, the role of microglia in TDP-43-mediated motor neuron degeneration remains poorly understood. In this study, we show that depletion of TDP-43 in microglia, but not in astrocytes, strikingly upregulates cyclooxygenase-2 (COX-2) expression and prostaglandin E2 (PGE2) production through the activation of MAPK/ERK signaling and initiates neurotoxicity. Moreover, we find that administration of celecoxib, a specific COX-2 inhibitor, greatly diminishes the neurotoxicity triggered by TDP-43-depleted microglia. Taken together, our results reveal a previously unrecognized non-cell-autonomous mechanism in TDP-43-mediated neurodegeneration, identifying COX-2-PGE2 as the molecular events of microglia- but not astrocyte-initiated neurotoxicity and identifying celecoxib as a novel potential therapy for TDP-43-linked ALS and possibly other types of ALS.
authors: Laboratory of Molecular Neuropathology, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China.
authors: Q
authors: Q
authors: Xia
authors: Laboratory of Molecular Neuropathology, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China.
authors: Q
authors: Q
authors: Hu
authors: Laboratory of Molecular Neuropathology, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China.
authors: H
authors: H
authors: Wang
authors: Laboratory of Molecular Neuropathology, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China.
authors: H
authors: H
authors: Yang
authors: Laboratory of Molecular Neuropathology, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China.
authors: F
authors: F
authors: Gao
authors: Laboratory of Molecular Neuropathology, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China.
authors: H
authors: H
authors: Ren
authors: Laboratory of Molecular Neuropathology, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China.
authors: D
authors: D
authors: Chen
authors: Key Laboratory of Brain Function and Disease, School of Life Sciences, University of Science & Technology of China, Chinese Academy of Sciences, Hefei, Anhui, China.
authors: C
authors: C
authors: Fu
authors: Laboratory of Molecular Neuropathology, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China.
authors: L
authors: L
authors: Zheng
authors: Laboratory of Molecular Neuropathology, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China.
authors: X
authors: X
authors: Zhen
authors: 1] Laboratory of Molecular Neuropathology, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China [2] Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China.
authors: Z
authors: Z
authors: Ying
authors: 1] Laboratory of Molecular Neuropathology, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China [2] Key Laboratory of Brain Function and Disease, School of Life Sciences, University of Science & Technology of China, Chinese Academy of Sciences, Hefei, Anhui, China.
authors: G
authors: G
authors: Wang
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D000068579:Celecoxib / Q000008:administration & dosage; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000096:biosynthesis* / Q000235:genetics; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015232:Dinoprostone / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000187:drug effects / Q000235:genetics; D009046:Motor Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009410:Nerve Degeneration / Q000188:drug therapy / Q000235:genetics / Q000473:pathology
chemical_list: D000068579:Celecoxib; D051546:Cyclooxygenase 2; D004268:DNA-Binding Proteins; D015232:Dinoprostone; D020929:Mitogen-Activated Protein Kinase Kinases; C578077:Tardbp protein, mouse; C077623:Ptgs2 protein, mouse