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Published on: June 22, 2022
Demethylase FTO-Mediated m6A Modification of lncRNA MEG3 Activates Neuronal Pyroptosis via NLRP3 Signaling in
Honglin Yan1, Wenxian Huang1, Jie Rao1
1Department of Pathology, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, People's Republic of China.
Abstract:
Neuronal death following ischemia is the primary cause of death and disability in patients with ischemic stroke. N6-methyladenosine (m6A) modification plays essential role in various physiological and pathological conditions, but its role and mechanism in ischemic neuronal death remain unclear. In the present study, neuronal pyroptosis was an important event in brain injury caused by ischemic stroke, and the upregulation of long non-coding RNA (lncRNA) maternally expressed gene 3 (MEG3) following cerebral ischemia was a key factor in activating ischemic neuronal pyroptosis via NLRP3/caspase-1/GSDMD signaling. Moreover, we first demonstrated that the demethylase fat mass and obesity-associated protein (FTO), which was decreased following ischemia, regulated MEG3 expression in an m6A-dependent manner by affecting its stability, thereby activating neuronal pyroptosis via NLRP3/caspase-1/GSDMD signaling, and ultimately leading to ischemic brain damage. Therefore, the present study provides new insights for the mechanism of ischemic stroke, and suggests that FTO may be a potential therapeutic target for ischemic stroke.
Insights
Neuronal pyroptosis drives ischemic stroke brain damage. Decreased FTO demethylase upregulates MEG3 lncRNA, activating this cell death pathway and suggesting FTO as a therapeutic target for stroke.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Ischemic stroke causes significant neuronal death, leading to disability.
- The role of N6-methyladenosine (m6A) modification in ischemic neuronal death is not fully understood.
- Neuronal pyroptosis is implicated in brain injury following ischemic stroke.
Purpose of the Study:
- To elucidate the mechanism of ischemic neuronal death involving m6A modification.
- To investigate the role of long non-coding RNA maternally expressed gene 3 (MEG3) in ischemic neuronal pyroptosis.
- To identify potential therapeutic targets for ischemic stroke.
Main Methods:
- Investigated neuronal pyroptosis as a key event in ischemic stroke brain injury.
- Examined the upregulation of MEG3 lncRNA and its role in activating the NLRP3/caspase-1/GSDMD signaling pathway.
- Assessed the regulation of MEG3 expression by the demethylase fat mass and obesity-associated protein (FTO) in an m6A-dependent manner.
Main Results:
- Neuronal pyroptosis is a critical mechanism in ischemic stroke-induced brain damage.
- Upregulated MEG3 lncRNA activates ischemic neuronal pyroptosis via the NLRP3/caspase-1/GSDMD pathway.
- Decreased FTO levels post-ischemia lead to MEG3 upregulation, promoting pyroptosis and brain injury.
Conclusions:
- The FTO/MEG3 axis plays a crucial role in ischemic neuronal death and stroke pathogenesis.
- Targeting FTO may offer a novel therapeutic strategy for mitigating ischemic stroke brain damage.
