C9-ALS-Associated Proline-Arginine Dipeptide Repeat Protein Induces Activation of NLRP3 Inflammasome of HMC3 Microglia Cells by Binding of Complement Component 1 Q Subcomponent-Binding Protein (C1QBP), and Syringin Prevents This Effect
Amyotrophic lateral sclerosis (ALS) is a fatal disease in which motor neurons gradually degenerate. The mutation of the <i>C9orf72</i> gene is the main genetic cause of ALS (C9-ALS). One of its specific pathological features is the production of proline-arginine (PR) dipeptide repeat pro...
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MDPI AG
2022-10-01
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| Online Access: | https://www.mdpi.com/2073-4409/11/19/3128 |
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| author | Ru-Huei Fu Chia-Wen Tsai Shao-Chih Chiu Shih-Ping Liu Yu-Ting Chiang Yun-Hua Kuo Woei-Cherng Shyu Shinn-Zong Lin |
| author_facet | Ru-Huei Fu Chia-Wen Tsai Shao-Chih Chiu Shih-Ping Liu Yu-Ting Chiang Yun-Hua Kuo Woei-Cherng Shyu Shinn-Zong Lin |
| author_sort | Ru-Huei Fu |
| collection | DOAJ |
| description | Amyotrophic lateral sclerosis (ALS) is a fatal disease in which motor neurons gradually degenerate. The mutation of the <i>C9orf72</i> gene is the main genetic cause of ALS (C9-ALS). One of its specific pathological features is the production of proline-arginine (PR) dipeptide repeat protein (DPR). In this study, we developed a PR-DPR (PR<sub>50</sub>)-expressing human HMC3 microglial cell model. We found that PR<sub>50</sub> mainly aggregates into spots in the nucleus and induces significant NLRP3 inflammasome activity. Moreover, mouse NSC-34 motor neuron cells treated with a conditional medium of PR<sub>50</sub>-expressing HMC3 cells (PR-CM) caused cell damage and apoptosis activity. However, R<sub>50</sub>-expressing HMC cells treated with MCC950 (an NLRP3 inhibitor) reversed this result. Furthermore, we identified complement component 1 q subcomponent-binding protein (C1QBP) as one of the interaction partners of PR<sub>50</sub>. The downregulation of C1QBP in HMC3 cells induces NLRP3 inflammasome activity similar to PR<sub>50</sub> expression. Finally, we found that syringin can block the interaction between PR<sub>50</sub> and C1QBP, and effectively reduce the PR<sub>50</sub>-induced NLRP3 inflammasome activity in HMC3 cells. This improves the apoptosis of NSC-34 cells caused by PR-CM. This study is the first to link PR<sub>50</sub>, C1QBP, and NLRP3 inflammasome activity in microglia and develop potential therapeutic strategies for syringin intervention in C9-ALS. |
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| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-09T21:52:39Z |
| publishDate | 2022-10-01 |
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| spelling | doaj.art-45445df8c1514b8d9c5407169073b1a62023-11-23T20:03:17ZengMDPI AGCells2073-44092022-10-011119312810.3390/cells11193128C9-ALS-Associated Proline-Arginine Dipeptide Repeat Protein Induces Activation of NLRP3 Inflammasome of HMC3 Microglia Cells by Binding of Complement Component 1 Q Subcomponent-Binding Protein (C1QBP), and Syringin Prevents This EffectRu-Huei Fu0Chia-Wen Tsai1Shao-Chih Chiu2Shih-Ping Liu3Yu-Ting Chiang4Yun-Hua Kuo5Woei-Cherng Shyu6Shinn-Zong Lin7Graduate Institute of Biomedical Sciences, China Medical University, Taichung 40402, TaiwanDepartment of Nutrition, China Medical University, Taichung 40402, TaiwanGraduate Institute of Biomedical Sciences, China Medical University, Taichung 40402, TaiwanGraduate Institute of Biomedical Sciences, China Medical University, Taichung 40402, TaiwanGraduate Institute of Biomedical Sciences, China Medical University, Taichung 40402, TaiwanGraduate Institute of Biomedical Sciences, China Medical University, Taichung 40402, TaiwanGraduate Institute of Biomedical Sciences, China Medical University, Taichung 40402, TaiwanBuddhist Tzu Chi Bioinnovation Center, Tzu Chi Foundation, Hualien 97002, TaiwanAmyotrophic lateral sclerosis (ALS) is a fatal disease in which motor neurons gradually degenerate. The mutation of the <i>C9orf72</i> gene is the main genetic cause of ALS (C9-ALS). One of its specific pathological features is the production of proline-arginine (PR) dipeptide repeat protein (DPR). In this study, we developed a PR-DPR (PR<sub>50</sub>)-expressing human HMC3 microglial cell model. We found that PR<sub>50</sub> mainly aggregates into spots in the nucleus and induces significant NLRP3 inflammasome activity. Moreover, mouse NSC-34 motor neuron cells treated with a conditional medium of PR<sub>50</sub>-expressing HMC3 cells (PR-CM) caused cell damage and apoptosis activity. However, R<sub>50</sub>-expressing HMC cells treated with MCC950 (an NLRP3 inhibitor) reversed this result. Furthermore, we identified complement component 1 q subcomponent-binding protein (C1QBP) as one of the interaction partners of PR<sub>50</sub>. The downregulation of C1QBP in HMC3 cells induces NLRP3 inflammasome activity similar to PR<sub>50</sub> expression. Finally, we found that syringin can block the interaction between PR<sub>50</sub> and C1QBP, and effectively reduce the PR<sub>50</sub>-induced NLRP3 inflammasome activity in HMC3 cells. This improves the apoptosis of NSC-34 cells caused by PR-CM. This study is the first to link PR<sub>50</sub>, C1QBP, and NLRP3 inflammasome activity in microglia and develop potential therapeutic strategies for syringin intervention in C9-ALS.https://www.mdpi.com/2073-4409/11/19/3128amyotrophic lateral sclerosis (ALS)<i>C9orf72</i>proline-arginine dipeptide repeat protein (PR-DPR)HMC3 microglia cellNLRP3 inflammasomemouse motor neuron NSC34 cell |
| spellingShingle | Ru-Huei Fu Chia-Wen Tsai Shao-Chih Chiu Shih-Ping Liu Yu-Ting Chiang Yun-Hua Kuo Woei-Cherng Shyu Shinn-Zong Lin C9-ALS-Associated Proline-Arginine Dipeptide Repeat Protein Induces Activation of NLRP3 Inflammasome of HMC3 Microglia Cells by Binding of Complement Component 1 Q Subcomponent-Binding Protein (C1QBP), and Syringin Prevents This Effect Cells amyotrophic lateral sclerosis (ALS) <i>C9orf72</i> proline-arginine dipeptide repeat protein (PR-DPR) HMC3 microglia cell NLRP3 inflammasome mouse motor neuron NSC34 cell |
| title | C9-ALS-Associated Proline-Arginine Dipeptide Repeat Protein Induces Activation of NLRP3 Inflammasome of HMC3 Microglia Cells by Binding of Complement Component 1 Q Subcomponent-Binding Protein (C1QBP), and Syringin Prevents This Effect |
| title_full | C9-ALS-Associated Proline-Arginine Dipeptide Repeat Protein Induces Activation of NLRP3 Inflammasome of HMC3 Microglia Cells by Binding of Complement Component 1 Q Subcomponent-Binding Protein (C1QBP), and Syringin Prevents This Effect |
| title_fullStr | C9-ALS-Associated Proline-Arginine Dipeptide Repeat Protein Induces Activation of NLRP3 Inflammasome of HMC3 Microglia Cells by Binding of Complement Component 1 Q Subcomponent-Binding Protein (C1QBP), and Syringin Prevents This Effect |
| title_full_unstemmed | C9-ALS-Associated Proline-Arginine Dipeptide Repeat Protein Induces Activation of NLRP3 Inflammasome of HMC3 Microglia Cells by Binding of Complement Component 1 Q Subcomponent-Binding Protein (C1QBP), and Syringin Prevents This Effect |
| title_short | C9-ALS-Associated Proline-Arginine Dipeptide Repeat Protein Induces Activation of NLRP3 Inflammasome of HMC3 Microglia Cells by Binding of Complement Component 1 Q Subcomponent-Binding Protein (C1QBP), and Syringin Prevents This Effect |
| title_sort | c9 als associated proline arginine dipeptide repeat protein induces activation of nlrp3 inflammasome of hmc3 microglia cells by binding of complement component 1 q subcomponent binding protein c1qbp and syringin prevents this effect |
| topic | amyotrophic lateral sclerosis (ALS) <i>C9orf72</i> proline-arginine dipeptide repeat protein (PR-DPR) HMC3 microglia cell NLRP3 inflammasome mouse motor neuron NSC34 cell |
| url | https://www.mdpi.com/2073-4409/11/19/3128 |
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