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长链非编码 RNA XIST 通过海绵吸附 miR-199a-3p 调控 Sp1/LRRK2 信号通路促进帕金森病进展。

LncRNA XIST sponges miR-199a-3p to modulate the Sp1/LRRK2 signal pathway to accelerate Parkinson's disease progression.

机构信息

Department of Neurosurgery, Second Xiangya Hospital of Central South University, Changsha 410011, Hunan Province, P.R. China.

出版信息

Aging (Albany NY). 2021 Jan 20;13(3):4115-4137. doi: 10.18632/aging.202378.

DOI:10.18632/aging.202378
PMID:33494069
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7906184/
Abstract

and models of Parkinson's disease were established to investigate the effects of the lncRNA XIST/miR-199a-3p/Sp1/LRRK2 axis. The binding between XIST and miR-199a-3p as well as miR-199a-3p and Sp1 were examined by luciferase reporter assay and confirmed by RNA immunoprecipitation analysis. Following the Parkinson's disease animal behavioural assessment by suspension and swim tests, the brain tissue injuries were evaluated by hematoxylin and eosin, TdT-mediated dUTP-biotin nick end labelling, and tyrosine hydroxylase stainings. The results indicated that miR-199a-3p expression was downregulated, whereas that of XIST, Sp1 and LRRK2 were upregulated in Parkinson's disease. Moreover, miR-199a-3p overexpression or XIST knockdown inhibited the cell apoptosis induced by MPP treatment and promoted cell proliferation. The neurodegenerative defects were significantly recovered by treating the cells with shXIST or shSp1, whereas miR-199a-3p inhibition or Sp1 and LRRK2 overexpression abrogated these beneficial effects. Furthermore, the results of our experiments confirmed the neuroprotective effects of shXIST and miR-199a-3p against MPTP-induced brain injuries, and the Parkinson's disease behavioural symptoms were effectively alleviated upon shXIST or miR-199a-3p treatment. In summary, the results of the present study showed that lncRNA XIST sponges miR-199a-3p to modulate Sp1 expression and further accelerates Parkinson's disease progression by targeting LRRK2.

摘要

并建立帕金森病模型，以研究 lncRNA XIST/miR-199a-3p/Sp1/LRRK2 轴的作用。通过荧光素酶报告基因检测和 RNA 免疫沉淀分析证实了 XIST 与 miR-199a-3p 以及 miR-199a-3p 与 Sp1 的结合。通过悬停和游泳试验进行帕金森病动物行为评估后，通过苏木精和伊红、TdT 介导的 dUTP-生物素切口末端标记和酪氨酸羟化酶染色评估脑组织损伤。结果表明，miR-199a-3p 的表达下调，而 XIST、Sp1 和 LRRK2 的表达上调。此外，miR-199a-3p 过表达或 XIST 敲低抑制 MPP 处理诱导的细胞凋亡，促进细胞增殖。用 shXIST 或 shSp1 处理细胞可显著恢复神经退行性缺陷，而 miR-199a-3p 抑制或 Sp1 和 LRRK2 过表达则消除了这些有益作用。此外，本实验结果证实了 shXIST 和 miR-199a-3p 对 MPTP 诱导的脑损伤的神经保护作用，并且 shXIST 或 miR-199a-3p 治疗可有效缓解帕金森病行为症状。总之，本研究结果表明，lncRNA XIST 作为 miR-199a-3p 的海绵，通过调节 Sp1 表达，进一步通过靶向 LRRK2 加速帕金森病的进展。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9721/7906184/66f5a83dafaf/aging-13-202378-g010.jpg
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