Correlation of the predisposition of Chinese children to cerebral palsy with nucleotide variation in pri-miR-124 that alters the non-canonical apoptosis pathway

• 来源期刊: 中国药理学报（英文版）
• 关键词: cerebral palsy miR-124 polymorphism non-canonical apoptosis pathway Chinese children
• 年，卷（期）: 2018,（9）
• 页码范围: 1453-1462
• 页数: 10页
• 语种: 英文
• DOI: 10.1038/aps.2017.211

摘要

Cerebral palsy (CP) is a group of non-progressive motor impairment syndromes caused by brain lesions during development. Herein, we investigated the relationship between nucleotide variations in a miRNA coding region and the predisposition of Chinese children to cerebral palsy. A total of 233 CP patients and 256 healthy participants were enrolled, and 60 children were selected from each group for plasma miRNA detection. We screened the coding regions of pri-miR-124-1, -2, and -3 using PCR and sequencing. The expression of miR-124 was determined by qRT-PCR. Luciferase assays and Western blots were used to confirm the regulation of target genes by miR-124. The function of miR-124 was further identified in SH-SY5Y cells by detecting cell viability and apoptosis. We revealed that the rare alleles T of rs3802169 and G of rs191727850 were found to be associated with an increased risk of cerebral palsy (OR=3.71, 95％ Cl 1.74-7.92 and OR=2.18, 95％ Cl 1.36-3.49, respectively). We further showed that the levels of mature miR-124 were down-regulated by the C-to-T variation in vitro. More importantly, the reduction of miR-124 resulting from the C-to-T change led to the less-efficient inhibition of the target genes ITGB1, LAMC1 and BECNl, which may play important roles during the development of the nervous system. Meanwhile, the reduction in the expression of miR-124 was also related to the increased nuclear translocation of apoptosis-inducing factor (AIF) under oxidative stress, thereby inducing more cell apoptosis. Our results suggest that one functional polymorphism in pri-miR-124-1 might contribute to the genetic predisposition of Chinese children to cerebral palsy by disrupting the production of miR-124, which consequently interfered in the expression and function of the target genes of miR-124.