Role of long noncoding RNA MEG3/miR-378/GRB2 axis in neuronal autophagy and neurological functional impairment in ischemic stroke
| Autor: | Ying Wei, Ting-Zhuang Yi, Xiao-Peng Luo, Qi-Sheng Luo, Fu-Gao Huang, Hong-Cheng Luo |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Ischemia Biochemistry Brain Ischemia Mice 03 medical and health sciences Autophagy medicine Animals Humans Gene silencing Molecular Biology Stroke Protein kinase B PI3K/AKT/mTOR pathway GRB2 Adaptor Protein Neurons MEG3 030102 biochemistry & molecular biology business.industry Molecular Bases of Disease Cell Biology medicine.disease Mice Mutant Strains Disease Models Animal MicroRNAs 030104 developmental biology RNA Long Noncoding business Neuron death Neuroscience Signal Transduction |
| Zdroj: | J Biol Chem |
| ISSN: | 0021-9258 |
| Popis: | Autophagy has been shown to maintain neural system homeostasis during stroke. However, the molecular mechanisms underlying neuronal autophagy in ischemic stroke remain poorly understood. This study aims to investigate the regulatory mechanisms of the pathway consisting of MEG3 (maternally expressed gene 3), microRNA-378 (miR-378), and GRB2 (growth factor receptor-bound protein 2) in neuronal autophagy and neurological functional impairment in ischemic stroke. A mouse model of the middle cerebral artery occluded–induced ischemic stroke and an in vitro model of oxygen-glucose deprivation–induced neuronal injury were developed. To understand the role of the MEG3/miR-378/GRB2 axis in the neuronal regulation, the expression of proteins associated with autophagy in neurons was measured by Western blotting analysis, and neuron death was evaluated using a lactate dehydrogenase leakage rate test. First, it was found that the GRB2 gene, up-regulated in middle cerebral artery occluded–operated mice and oxygen-glucose deprivation–exposed neurons, was a target gene of miR-378. Next, miR-378 inhibited neuronal loss and neurological functional impairment in mice, as well as neuronal autophagy and neuronal death by silencing of GRB2. Confirmatory in vitro experiments showed that MEG3 could specifically bind to miR-378 and subsequently up-regulate the expression of GRB2, which in turn suppressed the activation of Akt/mTOR pathway. Taken together, these findings suggested that miR-378 might protect against neuronal autophagy and neurological functional impairment and proposed that a MEG3/miR-378/GRB2 regulatory axis contributed to better understanding of the pathophysiology of ischemic stroke. |
| Databáze: | OpenAIRE |
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