Mutations in β-glucocerebrosidase (encoded by GBA1) cause Gaucher disease (GD), a lysosomal storage disorder, and increase the risk of developing Parkinson disease (PD). The pathogenetic relationship between the two disorders is unclear. Here, we characterised Ca(2+) release in fibroblasts from type I GD and PD patients together with age-matched, asymptomatic carriers, all with the common N370S mutation in β-glucocerebrosidase. We show that endoplasmic reticulum (ER) Ca(2+) release was potentiated in GD and PD patient fibroblasts but not in cells from asymptomatic carriers. ER Ca(2+) signalling was also potentiated in fibroblasts from aged healthy subjects relative to younger individuals but not further increased in aged PD patient cells. Chemical or molecular inhibition of β-glucocerebrosidase in fibroblasts and a neuronal cell line did not affect ER Ca(2+) signalling suggesting defects are independent of enzymatic activity loss. Conversely, lysosomal Ca(2+) store content was reduced in PD fibroblasts and associated with age-dependent alterations in lysosomal morphology. Accelerated remodelling of Ca(2+) stores by pathogenic GBA1 mutations may therefore feature in PD.

中文翻译：

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内质网和溶酶体 Ca²⁺ 储存在 GBA1 相关的帕金森病患者成纤维细胞中被重塑。

β-葡萄糖脑苷脂酶（由 GBA1 编码）的突变会导致戈谢病 (GD)，一种溶酶体贮积症，并增加患帕金森病 (PD) 的风险。这两种疾病之间的发病关系尚不清楚。在这里，我们描述了 I 型 GD 和 PD 患者以及年龄匹配的无症状携带者的成纤维细胞中 Ca(2+) 的释放，所有这些都具有 β-葡萄糖脑苷脂酶的常见 N370S 突变。我们显示内质网 (ER) Ca(2+) 释放在 GD 和 PD 患者成纤维细胞中增强，但在无症状携带者的细胞中没有增强。ER Ca(2+) 信号在老年健康受试者的成纤维细胞中也相对于年轻个体增强，但在老年 PD 患者细胞中没有进一步增加。成纤维细胞和神经元细胞系中 β-葡萄糖脑苷脂酶的化学或分子抑制不影响 ER Ca(2+) 信号传导，表明缺陷与酶活性丧失无关。相反，PD 成纤维细胞中溶酶体 Ca(2+) 储存量减少，并与溶酶体形态的年龄依赖性改变有关。因此，致病性 GBA1 突变对 Ca(2+) 储存的加速重塑可能在 PD 中具有特征。