The p.S85C-mutation in MATR3 impairs stress granule formation in Matrin-3 myopathy
The p.S85C-mutation in MATR3 impairs stress granule formation in Matrin-3 myopathy
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DOI：
10.1016/j.expneurol.2018.05.012
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发表时间：
2018-08-01
影响因子：
5.3
通讯作者：
Zierz, Stephan
中科院分区：
文献类型：
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作者：
Mensch, Alexander;Meinhardt, Beate;Zierz, Stephan
Matrin-3相关的远端肌病的特征主要是下肢的进行性远端无力。matrin-3（MATR 3）中的突变p.S85C已被确定为致病性改变，而导致肌肉疾病的具体分子机制尚未阐明。在本研究中，分析了来自6名患者的肌肉活检样品和来自4名MATR 3中携带p.S85C突变的患者的成纤维细胞。matrin-3定位或表达没有观察到特异性变化。与此相反，本地化的应力颗粒组件G3 BP 1和TIA 1被改变和增强的蛋白质以及RNA表达的G3 BP 1和TIA 1观察到在高度营养不良的组织。从远端肌肉取的肌肉活检标本的组织学变化明显。在患者来源的原代成纤维细胞中，使用亚砷酸钠处理监测细胞对氧化应激的反应。与健康对照相比，在施加氧化应激时显示应激颗粒形成的细胞分数在患者的成纤维细胞中显著较低。使用毒胡萝卜素对内质网应激获得了类似的结果。在应激颗粒阳性细胞与p.S85C突变的应激颗粒数量显着减少，而应激颗粒大小没有显着改变。一致地，在Matrin-3肌病衍生的成纤维细胞中，亚砷酸盐处理后的细胞活力似乎显著降低。总之，matrin-3中的p.S85C突变通过损害应激颗粒的形成和动力学来影响对细胞应激的反应。这可能有助于Matrin-3肌病的细胞损伤和肌肉营养不良的进展。
Matrin-3-related distal myopathy is characterized mainly by progressive distal weakness of the lower extremities. The mutation p.S85C in matrin-3 (MATR3) has been identified as disease-causing alteration, whereas the specific molecular mechanisms leading to the muscle disease have not been elucidated. In the present study, muscle biopsy samples from six patients and fibroblasts from four patients harboring p.S85C mutation in MATR3 were analyzed. No specific changes in matrin-3 localization or expression were observed. In contrast, localization of the stress granule components G3BP1 and TIA1 was altered and enhanced protein-as well as RNA expression of G3BP1 and TIA1 was observed in highly dystrophic tissues. Histological changes were pronounced in muscle biopsy specimen taken from distal muscles. In patient-derived primary fibroblasts, cellular response to oxidative stress was monitored using sodium arsenite treatment. The fraction of cells showing stress granule formation upon application of oxidative stress was significantly lower in patients' fibroblasts compared to healthy controls. Similar results were obtained for endoplasmatic reticulum stress using thapsigargin. Stress granule number in stress granule-positive cells with p.S85C mutation was significantly reduced, whereas stress granule size was not markedly altered. Consistently, cell viability upon arsenite treatment appeared significantly reduced in Matrin-3 myopathy derived fibroblasts. In summary, p.S85C mutation in matrin-3 affects the response to cellular stress by impairing stress granule formation and dynamics. This might contribute to cellular damage and progression of dystrophy in muscle of Matrin-3 myopathy.