Huang Qiong, Qin Dani, Chen Chunyan, Kang Yu, Chen Haocong, Xu Min, Fu Rao, Dong Xiaohua
Hongqiao International Institute of Medicine, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Neurology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Heliyon. 2024 Oct 1;10(21):e38822. doi: 10.1016/j.heliyon.2024.e38822. eCollection 2024 Nov 15.
Parkinson's disease (PD) is a progressive neurodegenerative disorder primarily driven by the degeneration of dopaminergic neurons, manifesting as hallmark symptoms such as muscle rigidity, tremors, and motor dysfunction, all of which severely compromise patients' quality of life. Increasing evidence highlights the critical role of long non-coding RNAs (lncRNAs) in PD pathogenesis. However, the specific involvement of SHANK2-AS3 in PD remains unclear. By reanalyzing the dysregulated lncRNAs from the GSE22491 dataset, we identified a significant upregulation of SHANK2-AS3 in PD patients compared to healthy controls. This finding was further validated in a new cohort of PD patients, where SHANK2-AS3 expression was notably elevated in peripheral blood samples. Additionally, we observed a marked increase in SHANK2-AS3 expression in MPTP-treated SH-SY5Y cells, a commonly used PD model. Functional assays demonstrated that SHANK2-AS3 knockdown attenuated MPTP-induced apoptosis, reduced reactive oxygen species (ROS) accumulation, and improved mitochondrial function. In contrast, SHANK2-AS3 overexpression exacerbated neuronal apoptosis. RNA sequencing and Western blot analyses revealed that the NF-κB signaling pathway is involved in SHANK2-AS3-mediated neuronal apoptosis. In summary, our findings suggest that SHANK2-AS3 plays a critical role in PD pathogenesis and represents a potential therapeutic target for mitigating neuronal damage in PD.
帕金森病（PD）是一种进行性神经退行性疾病，主要由多巴胺能神经元变性驱动，表现为肌肉僵硬、震颤和运动功能障碍等标志性症状，所有这些都严重损害患者的生活质量。越来越多的证据表明长链非编码RNA（lncRNAs）在PD发病机制中起关键作用。然而，SHANK2-AS3在PD中的具体作用仍不清楚。通过重新分析来自GSE22491数据集的失调lncRNAs，我们发现与健康对照相比，PD患者中SHANK2-AS3显著上调。这一发现在一组新的PD患者队列中得到进一步验证，其中外周血样本中SHANK2-AS3表达明显升高。此外，我们观察到在常用的PD模型MPTP处理的SH-SY5Y细胞中，SHANK2-AS3表达显著增加。功能试验表明，敲低SHANK2-AS3可减轻MPTP诱导的细胞凋亡，减少活性氧（ROS）积累，并改善线粒体功能。相反，SHANK2-AS3过表达加剧神经元凋亡。RNA测序和蛋白质印迹分析表明，NF-κB信号通路参与了SHANK2-AS3介导的神经元凋亡。总之，我们的研究结果表明，SHANK2-AS3在PD发病机制中起关键作用，是减轻PD神经元损伤的潜在治疗靶点。
