当前位置: X-MOL 学术Neurotoxicology › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
LncRNA SNHG1 promotes α-synuclein aggregation and toxicity by targeting miR-15b-5p to activate SIAH1 in human neuroblastoma SH-SY5Y cells
NeuroToxicology ( IF 3.4 ) Pub Date : 2017-12-05 , DOI: 10.1016/j.neuro.2017.12.001
Yuan Chen , Ya-jun Lian , Yun-qing Ma , Chuan-jie Wu , Ya-ke Zheng , Nan-chang Xie

Numerous long non-coding RNAs (lncRNAs) have been identified as aberrantly expressed in Parkinson’s disease (PD). However, limited knowledge is available concerning the roles of dysregulated lncRNAs and the underlying molecular regulatory mechanism in the pathological process of PD. In this study, we found that lncRNA small nucleolar RNA host gene 1 (SNHG1) and seven in absentia homolog 1 (SIAH1) were upregulated, but microRNA-15b-5p (miR-15b-5p) was downregulated in SH-SY5Y cells pretreated with MPP+, as well as in MPTP-induced mouse model of PD. Overexpression of SIAH1 enhanced cellular toxicity of α-synuclein in SH-SY5Y cells, as indicated by the reduction of cell viability and elevation of LDH release. The percentage of α-synuclein aggregate-positive cells and the number of α-synuclein aggregates per cell were increased in SH-SY5Y cells transfected with pcDNA-SIAH1, while decreased after transfection with short interfering RNA specific for SIAH1 (si-SIAH1). Bioinformatics and luciferase reporter assay revealed that SIAH1 was a direct target of miR-15b-5p. We also found that SNHG1 could directly bind to miR-15-5p and repress miR-15-5p expression. Upregulation of miR-15b-5p alleviated α-synuclein aggregation and apoptosis by targeting SIAH1 in SH-SY5Y cells overexpressing α-synuclein. Overexpression of SNHG1 enhanced, whereas SNHG1 knockdown inhibited α-synuclein aggregation and α-synuclein-induced apoptosis. Moreover, the neuroprotective effect of si-SNHG1 was abrogated by downregulation of miR-15b-5p. In summary, our data suggest that SNHG1, as a pathogenic factor, promotes α-synuclein aggregation and toxicity by targeting the miR-15b-5p/SIAH1 axis, contributing to a better understanding of the mechanisms of Lewy body formation and loss of dopaminergic neurons in PD.



中文翻译:

LncRNA SNHG1通过靶向miR-15b-5p激活人神经母细胞瘤SH-SY5Y细胞中的SIAH1来促进α-突触核蛋白的聚集和毒性

已经鉴定出许多在帕金森氏病(PD)中异常表达的长非编码RNA(lncRNA)。然而,关于PD的病理过程中失调的lncRNA的作用和潜在的分子调控机制的知识尚有限。在这项研究中,我们发现lncRNA小核仁RNA宿主基因1(SNHG1)和缺席同源1(SIAH1)中的七个被上调,而microRNA-15b-5p(miR-15b-5p)在经预处理的SH-SY5Y细胞中被下调MPP +以及MPTP诱导的PD小鼠模型中。SIAH1的过表达增强了SH-SY5Y细胞中α-突触核蛋白的细胞毒性,这表现为细胞活力的降低和LDH释放的升高。在用pcDNA-SIAH1转染的SH-SY5Y细胞中,α-突触核蛋白聚集阳性细胞的百分比和每个细胞的α-突触核蛋白聚集数量增加,而在用短时干扰RNA的SIAH1(si-SIAH1)转染后降低。生物信息学和萤光素酶报告基因检测表明,SIAH1是miR-15b-5p的直接靶标。我们还发现SNHG1可以直接与miR-15-5p结合并抑制miR-15-5p的表达。miR-15b-5p的上调通过靶向过表达α-突触核蛋白的SH-SY5Y细胞中的SIAH1减轻α-突触核蛋白的聚集和凋亡。SNHG1的过表达增强,而SNHG1敲低抑制α-突触核蛋白聚集和α-突触核蛋白诱导的细胞凋亡。此外,通过下调miR-15b-5p来消除si-SNHG1的神经保护作用。总而言之,我们的数据表明SNHG1,

更新日期:2017-12-05
down
wechat
bug