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RIPK1 activation in Mecp2-deficient microglia promotes inflammation and glutamate release in RTT.
- Source :
- Proceedings of the National Academy of Sciences of the United States of America; 2/6/2024, Vol. 121 Issue 6, p1-12, 35p
- Publication Year :
- 2024
-
Abstract
- Rett syndrome (RTT) is a devastating neurodevelopmental disorder primarily caused by mutations in the methyl-CpG binding protein 2 (Mecp2) gene. Here, we found that inhibition of Receptor-Interacting Serine/Threonine-Protein Kinase 1 (RIPK1) kinase ameliorated progression of motor dysfunction after onset and prolonged the survival of Mecp2-null mice. Microglia were activated early in myeloid Mecp2-deficient mice, which was inhibited upon inactivation of RIPK1 kinase. RIPK1 inhibition in Mecp2-deficient microglia reduced oxidative stress, cytokines production and induction of SLC7A11, SLC38A1, and GLS, which mediate the release of glutamate. Mecp2-deficient microglia release high levels of glutamate to impair glutamate-mediated excitatory neurotransmission and promote increased levels of GluA1 and GluA2/3 proteins in vivo, which was reduced upon RIPK1 inhibition. Thus, activation of RIPK1 kinase in Mecp2-deficient microglia may be involved both in the onset and progression of RTT. [ABSTRACT FROM AUTHOR]
- Subjects :
- MICROGLIA
GLUTAMIC acid
RETT syndrome
CARRIER proteins
GLUTAMATE transporters
Subjects
Details
- Language :
- English
- ISSN :
- 00278424
- Volume :
- 121
- Issue :
- 6
- Database :
- Complementary Index
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 175487402
- Full Text :
- https://doi.org/10.1073/pnas.2320383121