Parkinson’s disease (PD) is the second most common neurodegenerative disease, and mild cognitive impairment (MCI) is a well-established risk factor for the development of dementia in PD. A growing body of evidence suggests that low expression of glucocerebrosidase (GBA) promotes the transmission of α-synuclein (α-Syn) interpolymers and the progression of PD. However, how GBA mutations affect the pathogenesis of PD via abnormal aggregation of α-Syn is unclear, and no clinically valid PD-MCI genetic markers have been identified. Here, we first located a GBA eQTL, rs12411216, by analysing DHS, eQTL SNP, and transcription factor binding site data using the UCSC database. Subsequently, we found that rs12411216 was significantly associated with PD-MCI (P < 0.05) in 306 PD patients by genotyping. In exploring the relationship between rs12411216 and GBA expression, the SNP was found to be associated with GBA expression in 50 PD patients through qPCR verification. In a further CRISPR/Cas9-mediated genome editing module, the SNP was identified to cause a decrease in GBA expression, weaken enzymatic activity and enhance the abnormal aggregation of α-Syn in SH-SY5Y cells. Additionally, using an electrophoretic mobility shift assay, we confirmed that the binding efficiency of transcription factor E2F4 was affected by the rs12411216 SNP. In conclusion, our results showed that rs12411216 regulated GBA expression, supporting its potential role as a PD-MCI genetic biomarker and highlighting novel mechanisms underlying Parkinson’s disease.

中文翻译：

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GBA中帕金森氏病伴轻度认知障碍患者的致病变异的特征。

帕金森氏病（PD）是第二大最常见的神经退行性疾病，轻度认知障碍（MCI）是PD中痴呆发展的公认危险因素。越来越多的证据表明，葡糖脑苷脂酶（GBA）的低表达会促进α-突触核蛋白（α-Syn）互聚物的传播和PD的发展。然而，尚不清楚GBA突变如何通过α-Syn异常聚集影响PD的发病机理，并且尚未发现临床上有效的PD-MCI遗传标记。在这里，我们首先使用UCSC数据库分析了DHS，eQTL SNP和转录因子结合位点数据，从而找到了GBA eQTL rs12411216。随后，通过基因分型，我们发现rs12411216与306名PD患者的PD-MCI显着相关（P <0.05）。在探索rs12411216与GBA表达之间的关系时，通过qPCR验证发现SNP与50名PD患者的GBA表达相关。在另一个由CRISPR / Cas9介导的基因组编辑模块中，发现SNP导致GBA表达减少，酶活性减弱以及SH-SY5Y细胞中α-Syn异常聚集。此外，使用电泳迁移率变动分析，我们确认了rs12411216 SNP影响转录因子E2F4的结合效率。总之，我们的结果表明rs12411216调节GBA表达，支持其作为PD-MCI遗传生物标记物的潜在作用，并突出显示了帕金森氏病的潜在新机制。在另一个由CRISPR / Cas9介导的基因组编辑模块中，发现SNP导致GBA表达减少，酶活性减弱以及SH-SY5Y细胞中α-Syn异常聚集。此外，使用电泳迁移率变动分析，我们确认了rs12411216 SNP影响转录因子E2F4的结合效率。总之，我们的结果表明rs12411216调节GBA表达，支持其作为PD-MCI遗传生物标记物的潜在作用，并突出显示了帕金森氏病的潜在新机制。在另一个由CRISPR / Cas9介导的基因组编辑模块中，发现SNP导致GBA表达减少，酶活性减弱以及SH-SY5Y细胞中α-Syn异常聚集。此外，使用电泳迁移率变动分析，我们确认了rs12411216 SNP影响转录因子E2F4的结合效率。总之，我们的结果表明rs12411216调节GBA表达，支持其作为PD-MCI遗传生物标记物的潜在作用，并强调了帕金森氏病的潜在新机制。我们证实，转录因子E2F4的结合效率受rs12411216 SNP的影响。总之，我们的结果表明rs12411216调节GBA表达，支持其作为PD-MCI遗传生物标记物的潜在作用，并强调了帕金森氏病的潜在新机制。我们证实，转录因子E2F4的结合效率受rs12411216 SNP的影响。总之，我们的结果表明rs12411216调节GBA表达，支持其作为PD-MCI遗传生物标记物的潜在作用，并强调了帕金森氏病的潜在新机制。