Kołowa cząsteczka RNA SLC8A1 z astrocytów wspomaga zapalenie mózgu poprzez aktywację piroptoza w epilepsji skroniowej
Astrocytic circular RNA SLC8A1 boosted CEBPB/NLRP3-triggered pyroptosis by stabilizing PTBP1 to drive neuroinflammation in temporal lobe epilepsy
W skrócie
Badanie wykazało, że specjalna cząsteczka RNA (circSLC8A1) jest podwyższona w mózgach myszy z epilepsją skroniową i znajduje się głównie w astrocytach (pomocniczych komórkach mózgu). Ta cząsteczka powoduje niszczenie komórek oraz zapalenie, co pogarsza epilepsję. Naukowcy odkryli nowy mechanizm, w którym circSLC8A1 chroni białko PTBP1, które następnie aktywuje inne białka prowadzące do zapalenia i śmierci astrocytów, a zablokowanie tego procesu mogłoby być nowym sposobem leczenia epilepsji.
Oryginalny abstract (angielski)
BACKGROUND: Temporal lobe epilepsy (TLE) is the most common form of chronic focal epilepsy in adults and is often associated with pharmacoresistance and cognitive impairment. Accumulating evidence suggests that neuroinflammation and glial cell dysfunction play pivotal roles in TLE pathogenesis. However, the molecular mechanisms underlying astrocyte-mediated inflammation remain poorly defined. METHODS: A mouse model of TLE was established using kainic acid-induced seizures. circSLC8A1 expression and cell distribution were assessed in the hippocampus by RT-qPCR, in situ hybridization, and immunostaining. Primary astrocytes were manipulated to overexpress or knock down circSLC8A1, and inflammatory and pyroptotic responses were evaluated. RNA pull-down and RNA immunoprecipitation (RIP) assays were performed to identify RNA-binding partners. mRNA stability assays and dual-luciferase reporter experiments were used to validate the circSLC8A1/PTBP1/CEBPB regulatory axis. RESULTS: circSLC8A1 was significantly upregulated in the hippocampus of TLE mice and predominantly localized in astrocytes. Gain- and loss-of-function studies demonstrated a promotive role of circSLC8A1 in astrocytic inflammation and pyroptosis. Mechanistically, circSLC8A1 directly interacted with the RNA-binding protein PTBP1, protecting it from ubiquitin/proteasome-dependent degradation. The circSLC8A1/PTBP1 complex enhanced the stability of CEBPB mRNA. CEBPB subsequently promoted NLRP3 inflammasome activation, contributing to pyroptosis in astrocytes. CONCLUSION: Our findings identify a novel circSLC8A1/PTBP1/CEBPB signaling axis that mediates astrocytic inflammation and pyroptosis in TLE. Targeting circSLC8A1 may represent a promising therapeutic strategy for epilepsy.