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miR-142-3p 通过负向调控 C9orf72 减轻帕金森病中的神经元凋亡。

miR-142-3p alleviates neuronal apoptosis in Parkinson's disease via negatively regulating C9orf72.

机构信息

Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, School of Basic Medical Sciences, Nanjing Medical University, 818 Tianyuan East Road, Nanjing, Jiangsu 211166, China.

Department of Pharmacology, Nanjing University of Chinese Medicine, 138 Xianlin Avenue, Nanjing, Jiangsu 210023, China.

出版信息

Neurosci Lett. 2024 Jul 27;836:137887. doi: 10.1016/j.neulet.2024.137887. Epub 2024 Jun 26.

Abstract

Although microRNA (miRNA) have important clinical prospects in the early diagnosis and treatment of PD, the functions and mechanisms of miRNAs in PD models remain poorly defined. In this study, we screened 9 miRNAs that differently expressed in PD patients and found that miR-142-3p expression was downregulated in both animal and cell models of PD. We showed that overexpression of miR-142-3p significantly alleviates the neuronal damage induced by MPP, while knockdown of miR-142-3p exacerbates the neuronal damage caused by MPP. We further found that miR-142-3p targets and inhibits the expression of C9orf72. Knockdown of C9orf72 mitigated neuronal autophagy dysfunction by reducing excessive activation of the AKT/mTOR pathway after MPP stimulation, thereby exerted neuroprotective effects. This study reveals that miR-142-3p protects neuron in PD pathogenesis via negatively regulating C9orf72 and enhancing autophagy. Our findings provides an insight into the development of potential biomarkers and therapeutic targets for PD.

摘要

虽然 microRNA (miRNA) 在 PD 的早期诊断和治疗中有重要的临床前景,但 miRNA 在 PD 模型中的功能和机制仍未明确。在本研究中,我们筛选了在 PD 患者中差异表达的 9 个 miRNA,发现 miR-142-3p 在 PD 的动物和细胞模型中表达均下调。我们表明,miR-142-3p 的过表达可显著减轻 MPP 诱导的神经元损伤,而 miR-142-3p 的敲低则加剧了 MPP 引起的神经元损伤。我们进一步发现,miR-142-3p 靶向并抑制 C9orf72 的表达。敲低 C9orf72 通过减少 MPP 刺激后 AKT/mTOR 通路的过度激活,减轻神经元自噬功能障碍,从而发挥神经保护作用。本研究揭示了 miR-142-3p 通过负调控 C9orf72 和增强自噬来保护 PD 发病机制中的神经元。我们的研究结果为 PD 的潜在生物标志物和治疗靶点的开发提供了新的见解。

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