Glucosylceramide accumulation in microglia triggers STING-dependent neuroinflammation and neurodegeneration in mice
Mutations in the gene encoding the lysosomal enzyme glucocerebrosidase (GCase) are responsible for Gaucher disease (GD) and are considered the strongest genetic risk factor for Parkinson's disease (PD) and Lewy body dementia (LBD). GCase deficiency leads to extensive accumulation of glucosylceramides (GCs) in cells and contributes to the neuropathology of GD, PD, and LBD by triggering chronic neuroinflammation. Here, we investigated the mechanisms by which GC accumulation induces neuroinflammation. We found that GC accumulation within microglia induced by pharmacological inhibition of GCase triggered STING-dependent inflammation, which contributed to neuronal loss both in vitro and in vivo. GC accumulation in microglia induced mitochondrial DNA (mtDNA) leakage to the cytosol to trigger STING-dependent inflammation. Rapamycin, a compound that promotes lysosomal activity, improved mitochondrial function, thereby decreasing STING signaling. Furthermore, lysosomal damage caused by GC accumulation led to defects in the degradation of activated STING, further exacerbating inflammation mediated by microglia. Thus, limiting STING activity may be a strategy to suppress neuroinflammation caused by GCase deficiency.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:17 |
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| Enthalten in: |
Science signaling - 17(2024), 829 vom: 26. März, Seite eadk8249 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Wang, Rui [VerfasserIn] |
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| Links: |
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| Themen: |
Alpha-Synuclein |
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| Anmerkungen: |
Date Completed 28.03.2024 Date Revised 29.03.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1126/scisignal.adk8249 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM370204344 |
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| 520 | |a Mutations in the gene encoding the lysosomal enzyme glucocerebrosidase (GCase) are responsible for Gaucher disease (GD) and are considered the strongest genetic risk factor for Parkinson's disease (PD) and Lewy body dementia (LBD). GCase deficiency leads to extensive accumulation of glucosylceramides (GCs) in cells and contributes to the neuropathology of GD, PD, and LBD by triggering chronic neuroinflammation. Here, we investigated the mechanisms by which GC accumulation induces neuroinflammation. We found that GC accumulation within microglia induced by pharmacological inhibition of GCase triggered STING-dependent inflammation, which contributed to neuronal loss both in vitro and in vivo. GC accumulation in microglia induced mitochondrial DNA (mtDNA) leakage to the cytosol to trigger STING-dependent inflammation. Rapamycin, a compound that promotes lysosomal activity, improved mitochondrial function, thereby decreasing STING signaling. Furthermore, lysosomal damage caused by GC accumulation led to defects in the degradation of activated STING, further exacerbating inflammation mediated by microglia. Thus, limiting STING activity may be a strategy to suppress neuroinflammation caused by GCase deficiency | ||
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| 700 | 1 | |a Cao, Yifan |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Zhixiong |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Yajing |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Xiying |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Lele |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Jin |e verfasserin |4 aut | |
| 700 | 1 | |a Xu, Hao |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Dan |e verfasserin |4 aut | |
| 700 | 1 | |a Mu, Chenchen |e verfasserin |4 aut | |
| 700 | 1 | |a Hao, Zongbing |e verfasserin |4 aut | |
| 700 | 1 | |a Qin, Song |e verfasserin |4 aut | |
| 700 | 1 | |a Ren, Haigang |e verfasserin |4 aut | |
| 700 | 1 | |a Han, Junhai |e verfasserin |4 aut | |
| 700 | 1 | |a Fang, Ming |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Guanghui |e verfasserin |4 aut | |
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