School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India.
College of Health Sciences, Department of Biomedical Sciences, Qatar University, Doha, Qatar.
Metab Brain Dis. 2018 Dec;33(6):1835-1847. doi: 10.1007/s11011-018-0286-3. Epub 2018 Jul 6.
Gaucher's disease (GD) is a genetic disorder in which glucocerebroside accumulates in cells and specific organs. It is broadly classified into type I, type II and type III. Patients with GD are at high risk of Parkinson's disease (PD), and the clinical and pathological presentation of GD patients with PD is almost identical to idiopathic PD. Several experimental models like cell culture, animal models, and transgenic mice models were used to understand the molecular mechanism behind GD and PD association; however, such mechanism remains unclear. In this context, based on literature reports, we identified the most common mutations K198T, E326K, T369M, N370S, V394L, D409H, L444P, and R496H, in the Glucosylceramidase (GBA) protein that are known to cause GD1, and represent a risk of developing PD. However, to date, no computational analyses have designed to elucidate the potential functional role of GD mutations with increased risk of PD. The present computational pipeline allows us to understand the structural and functional significance of these GBA mutations with PD. Based on the published data, the most common and severe mutations were E326K, N370S, and L444P, which further selected for our computational analysis. PredictSNP and iStable servers predicted L444P mutant to be the most deleterious and responsible for the protein destabilization, followed by the N370S mutation. Further, we used the structural analysis and molecular dynamics approach to compare the most frequent deleterious mutations (N370S and L444P) with the mild mutation E326K. The structural analysis demonstrated that the location of E326K and N370S in the alpha helix region of the protein whereas the mutant L444P was in the starting region of the beta sheet, which might explain the predicted pathogenicity level and destabilization effect of the L444P mutant. Finally, Molecular Dynamics (MD) at 50 ns showed the highest deviation and fluctuation pattern in the L444P mutant compared to the two mutants E326K and N370S and the native protein. This was consistent with more loss of intramolecular hydrogen bonds and less compaction of the radius of gyration in the L444P mutant. The proposed study is anticipated to serve as a potential platform to understand the mechanism of the association between GD and PD, and might facilitate the process of drug discovery against both GD and PD.
戈谢病（GD）是一种遗传性疾病，其中葡糖脑苷脂在细胞和特定器官中积累。它广泛分为 I 型、II 型和 III 型。GD 患者患帕金森病（PD）的风险很高，且 GD 合并 PD 患者的临床和病理表现与特发性 PD 几乎相同。已经使用了几种实验模型，如细胞培养、动物模型和转基因小鼠模型，来了解 GD 和 PD 之间关联的分子机制；然而，这种机制尚不清楚。在这种情况下，根据文献报告，我们在葡萄糖脑苷脂酶（GBA）蛋白中鉴定出了最常见的突变 K198T、E326K、T369M、N370S、V394L、D409H、L444P 和 R496H，这些突变已知会导致 GD1，并代表 PD 发病的风险。然而，迄今为止，还没有针对计算分析来阐明具有增加 PD 风险的 GD 突变的潜在功能作用。本计算流程使我们能够理解这些与 PD 相关的 GBA 突变的结构和功能意义。根据已发表的数据，最常见和最严重的突变是 E326K、N370S 和 L444P，这些突变进一步被选为我们的计算分析。PredictSNP 和 iStable 服务器预测 L444P 突变体是最具破坏性的，并导致蛋白质不稳定，其次是 N370S 突变。此外，我们使用结构分析和分子动力学方法来比较最常见的有害突变（N370S 和 L444P）与轻度突变 E326K。结构分析表明，E326K 和 N370S 位于蛋白质的α螺旋区域，而突变体 L444P 位于β片层的起始区域，这可能解释了 L444P 突变体的预测致病性水平和失稳效应。最后，50ns 的分子动力学（MD）显示，与两个突变体 E326K 和 N370S 以及天然蛋白相比，L444P 突变体的偏差和波动模式最大。这与 L444P 突变体中更多的分子内氢键丧失和更少的回转半径紧凑相一致。预计该研究将作为一个潜在的平台，以了解 GD 和 PD 之间关联的机制，并可能有助于 GD 和 PD 药物发现的进程。
