N-acetyl-L-cysteine prevents stress-induced desmin aggregation in cellular models of desminopathy.
N-acetyl-L-cysteine prevents stress-induced desmin aggregation in cellular models of desminopathy.
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DOI：
10.1371/journal.pone.0076361
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Batonnet-Pichon S
中科院分区：
文献类型：
--
作者：
Segard BD;Delort F;Bailleux V;Simon S;Leccia E;Gausseres B;Briki F;Vicart P;Batonnet-Pichon S
人类结蛋白基因内的突变导致称为结蛋白病的肌原纤维肌病的亚类。然而，一个单一的遗传突变可以在一个家庭中产生不同的表型，这表明环境因素影响疾病状态。虽然几种小鼠模型已被用于调查器官特异性desminopathies，一个更一般的机制的角度是需要推进我们的知识对病人的治疗。为了提高我们对疾病病理学的理解，我们开发了细胞模型来观察疾病病理学早期阶段的结蛋白行为，例如，在等基因背景下，细胞质结蛋白聚集体形成后。我们使用Tet-On Advanced®表达系统在C2 C12细胞中克隆野生型和三种突变结蛋白cDNA。基于在结蛋白内的定位和在瞬时实验中形成聚集体的能力选择突变，如下：DesS 46 Y（头部结构域;低聚集）、DesD 399 Y（中心杆结构域;高聚集）和DesS 460 I（尾部结构域;中等聚集）。将这些蛋白质引入C2 C12背景中使我们能够比较结蛋白变体之间的差异以及确定外部应力对聚集的作用。三种不同类型的应力，可能遇到肌肉活动期间，被引入到细胞模型热（热休克），氧化还原相关（H2 O2和氯化镉），和机械（拉伸）应力后，聚集进行了测量。含有变异DesD 399 Y的细胞对应激更敏感，导致显著的细胞质核周聚集。然后，我们评估了生化化合物的能力，以防止这种聚集，应用地塞米松（诱导剂的热休克蛋白），非瑟酮或N-乙酰-L-半胱氨酸（抗氧化剂）应激诱导前。有趣的是，N-乙酰基-L-半胱氨酸预处理防止DesD 399 Y聚集在大多数压力。N-乙酰-L-半胱氨酸最近被描述为与硒蛋白N或ryanodin受体缺陷相关的肌病中有前途的抗氧化剂。我们的研究结果表明，这种药物值得在动物模型中进行进一步研究，以加速其作为DesD 399 Y相关结蛋白病治疗的潜在发展。
Mutations within the human desmin gene are responsible for a subcategory of myofibrillar myopathies called desminopathies. However, a single inherited mutation can produce different phenotypes within a family, suggesting that environmental factors influence disease states. Although several mouse models have been used to investigate organ-specific desminopathies, a more general mechanistic perspective is required to advance our knowledge toward patient treatment. To improve our understanding of disease pathology, we have developed cellular models to observe desmin behaviour in early stages of disease pathology, e.g., upon formation of cytoplasmic desmin aggregates, within an isogenic background. We cloned the wildtype and three mutant desmin cDNAs using a Tet-On Advanced® expression system in C2C12 cells. Mutations were selected based on positioning within desmin and capacity to form aggregates in transient experiments, as follows: DesS46Y (head domain; low aggregation), DesD399Y (central rod domain; high aggregation), and DesS460I (tail domain; moderate aggregation). Introduction of these proteins into a C2C12 background permitted us to compare between desmin variants as well as to determine the role of external stress on aggregation. Three different types of stress, likely encountered during muscle activity, were introduced to the cell models—thermal (heat shock), redox-associated (H2O2 and cadmium chloride), and mechanical (stretching) stresses—after which aggregation was measured. Cells containing variant DesD399Y were more sensitive to stress, leading to marked cytoplasmic perinuclear aggregations. We then evaluated the capacity of biochemical compounds to prevent this aggregation, applying dexamethasone (an inducer of heat shock proteins), fisetin or N-acetyl-L-cysteine (antioxidants) before stress induction. Interestingly, N-acetyl-L-cysteine pre-treatment prevented DesD399Y aggregation during most stress. N-acetyl-L-cysteine has recently been described as a promising antioxidant in myopathies linked to selenoprotein N or ryanodin receptor defects. Our findings indicate that this drug warrants further study in animal models to speed its potential development as a therapy for DesD399Y-linked desminopathies.
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DOI：
10.1097/nen.0b013e3181256b4c
发表时间：
2007-08-01
影响因子：
3.2
作者：
Biol, Anna Janue;Odena, Maria Antonia;Ferrer, Isidro
通讯作者：
Ferrer, Isidro
DOI：
10.1080/15287390590925447
发表时间：
2005-05-14
影响因子：
2.6
作者：
Croute, F;Beau, B;Soleilhavoup, JP
通讯作者：
Soleilhavoup, JP
影响因子：
3.4
作者：
Kreplak, Laurent;Herrmann, Harald;Aebi, Ueli
通讯作者：
Aebi, Ueli
影响因子：
3.7
作者：
Chourbagi, Oussama;Bruston, Francine;Agbulut, Onnik
通讯作者：
Agbulut, Onnik
影响因子：
3.9
作者：
Bar, Harald;Goudeau, Bertrand;Herrmann, Harald
通讯作者：
Herrmann, Harald