Department of Geriatric Neurology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
Clin Exp Pharmacol Physiol. 2020 Mar;47(3):372-382. doi: 10.1111/1440-1681.13212. Epub 2019 Dec 15.
MicroRNAs (miRNAs) have been shown to have complicated implications in the pathogenesis of Parkinson's disease (PD). However, the role of miR-29c and the underlying mechanism in the development of PD remain not well understood. In this work, the MPTP-treated mice or MPP -intoxicated SH-SY5Y cells were established as an in vivo or in vitro PD model. Then the specific agomir of miR-29c was employed to examine its biological function on PD progress. We found that miR-29c was down-expressed but SP1 was high-expressed in substantia nigra pars compacta (SNpc) of MPTP-induced PD mice. Overexpression of miR-29c attenuated dopaminergic neuron loss and α-synuclein accumulation in SNpc of PD mice. Furthermore, the increments of pro-inflammatory cytokines (TNF-α, IL-1β and IL-6) and TUNEL-positive apoptotic cells in MPTP-treated mice were ameliorated by miR-29c. Similarly, in SH-SY5Y cell models of PD, we also found that miR-29c inhibited inflammatory cytokine production, reduced apoptotic rate and suppressed pro-apoptotic regulator activity. In addition, the increased expression of SP1 in PD models was found to be inhibited by miR-29c. Luciferase reporter assay confirmed that SP1 was complementary with miR-29c. Knockdown of SP1 with siRNA restored α-synuclein accumulation, inflammation and apoptosis in MPP -induced SH-SY5Y cells. Collectively, this current work presents that miR-29c may directly target SP1 to protect against the neuroinflammatory and apoptotic responses in PD, providing a potential biomarker for PD diagnosis and treatment.
微小 RNA（miRNAs）在帕金森病（PD）的发病机制中具有复杂的影响。然而，miR-29c 在 PD 发展中的作用及其潜在机制仍未完全阐明。在这项工作中，采用 MPTP 处理的小鼠或 MPP 诱导的 SH-SY5Y 细胞作为体内或体外 PD 模型。然后，采用 miR-29c 的特异性激动剂来研究其对 PD 进展的生物学功能。我们发现，miR-29c 在 MPTP 诱导的 PD 小鼠黑质致密部（SNpc）中表达下调，而 SP1 表达上调。miR-29c 的过表达减轻了 PD 小鼠 SNpc 中多巴胺能神经元的丢失和α-突触核蛋白的积累。此外，miR-29c 改善了 MPTP 处理小鼠中促炎细胞因子（TNF-α、IL-1β 和 IL-6）和 TUNEL 阳性凋亡细胞的增加。同样，在 PD 的 SH-SY5Y 细胞模型中，我们还发现 miR-29c 抑制了炎症细胞因子的产生，降低了细胞凋亡率，并抑制了促凋亡调节剂的活性。此外，在 PD 模型中发现 SP1 的增加表达被 miR-29c 抑制。荧光素酶报告基因检测证实 SP1 与 miR-29c 互补。用 siRNA 敲低 SP1 可恢复 MPP 诱导的 SH-SY5Y 细胞中α-突触核蛋白的积累、炎症和凋亡。总之，本研究表明，miR-29c 可能通过直接靶向 SP1 来保护 PD 中的神经炎症和凋亡反应，为 PD 的诊断和治疗提供了一个潜在的生物标志物。
