| Autor: |
Wang, Rui, Sun, Hongyang, Cao, Yifan, Zhang, Zhixiong, Chen, Yajing, Wang, Xiying, Liu, Lele, Wu, Jin, Xu, Hao, Wu, Dan, Mu, Chenchen, Hao, Zongbing, Qin, Song, Ren, Haigang, Han, Junhai, Fang, Ming, Wang, Guanghui |
| Předmět: |
|
| Zdroj: |
Science Signaling; 3/26/2024, Vol. 17 Issue 829, p1-16, 16p |
| Abstrakt: |
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. Editor's summary: Loss of the enzyme glucocerebrosidase causes Gaucher disease, which features systemic buildup of the lipid glucosylceramide, neuroinflammation, and increased risk of Parkinson's disease. Wang et al. found that pharmacological inhibition of glucocerebrosidase in mice activated inflammatory microglia in the cortex. Glucosylceramide accumulation in microglia induced the release of mitochondrial DNA and impaired lysosomal function. As a result, STING signaling was activated and the clearance of STING and damaged mitochondria was impaired, thereby fueling neurodegenerative inflammation. Treating mice with a STING inhibitor or an enhancer of lysosomal function was neuroprotective, suggesting potential therapeutic approaches in patients. —Leslie K. Ferrarelli [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
|
