| First Author | Hashimoto S | Year | 2023 |
| Journal | Sci Rep | Volume | 13 |
| Issue | 1 | Pages | 1109 |
| PubMed ID | 36670138 | Mgi Jnum | J:333385 |
| Mgi Id | MGI:7430443 | Doi | 10.1038/s41598-023-27653-w |
| Citation | Hashimoto S, et al. (2023) Neuronal glutathione loss leads to neurodegeneration involving gasdermin activation. Sci Rep 13(1):1109 |
| abstractText | Accumulating evidence suggests that glutathione loss is closely associated with the progression of neurodegenerative disorders. Here, we found that the neuronal conditional-knockout (KO) of glutamyl-cysteine-ligase catalytic-subunit (GCLC), a rate-limiting enzyme for glutathione synthesis, induced brain atrophy accompanied by neuronal loss and neuroinflammation. GCLC-KO mice showed activation of C1q, which triggers engulfment of neurons by microglia, and disease-associated-microglia (DAM), suggesting that activation of microglia is linked to the neuronal loss. Furthermore, gasdermins, which regulate inflammatory form of cell death, were upregulated in the brains of GCLC-KO mice, suggesting the contribution of pyroptosis to neuronal cell death in these animals. In particular, GSDME-deficiency significantly attenuated the hippocampal atrophy and changed levels of DAM markers in GCLC-KO mice. Finally, we found that the expression of GCLC was decreased around amyloid plaques in App(NL-G-F) AD model mice. App(NL-G-F) mouse also exhibited inflammatory events similar to GCLC-KO mouse. We propose a mechanism by which a vicious cycle of oxidative stress and neuroinflammation enhances neurodegenerative processes. Furthermore, GCLC-KO mouse will serve as a useful tool to investigate the molecular mechanisms underlying neurodegeneration and in the development of new treatment strategies to address neurodegenerative diseases. |
