Modulation of muscle redox and protein aggregation rescues lethality caused by mutant lamins.
Modulation of muscle redox and protein aggregation rescues lethality caused by mutant lamins.
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肌肉氧化还原和蛋白质聚集的调节可挽救突变核纤层蛋白引起的致命性。
DOI：
10.1016/j.redox.2021.102196
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发表时间：
2021-11-25
期刊：
影响因子：
11.4
通讯作者：
Wallrath LL
中科院分区：
文献类型：
--
作者：
Coombs GS;Rios-Monterrosa JL;Lai S;Dai Q;Goll AC;Ketterer MR;Valdes MF;Uche N;Benjamin IJ;Wallrath LL
人类LMNA基因的突变会导致一系列被称为核纤层蛋白病的疾病，包括肌肉萎缩症和扩张型心肌病。LMNA基因编码核纤层蛋白，在核膜内侧形成网状结构的丝状蛋白。突变核纤层蛋白如何导致肌肉疾病还不清楚，目前治疗选择有限。为了了解突变核纤层蛋白的病理功能，以便开发治疗方法，我们产生了新的果蝇模型和人iPS细胞衍生的心肌细胞。在果蝇模型中，肌肉特异性表达的突变核纤层蛋白引起核膜缺陷，细胞质蛋白质聚集，激活Nrf 2/Keap 1氧化还原途径，和还原应激。这些缺陷降低了幼虫的能动性，并导致蛹期死亡。表达突变核纤层蛋白的患者来源的心肌细胞显示核被膜变形。果蝇模型允许在生物体水平上进行遗传和药理学操作。增加自噬、降低Nrf 2/Keap 1信号传导或降低还原当量的遗传干预部分抑制了突变核纤层蛋白引起的致死性。此外，用双羟萘酸（一种抑制产生NADPH的苹果酸酶的化合物）治疗苍蝇，部分抑制了致死率。总之，这些研究已经确定了多种新的因子作为LMNA相关肌营养不良症的潜在治疗靶点。LMNA肌营养不良症的果蝇模型表现出氧化还原失衡。核纤层蛋白的三个结构域中的氨基酸取代引起还原性应激。iPS细胞衍生的心肌细胞显示出对NAC处理的改变的反应。自噬调节因子的遗传操作抑制突变核纤层蛋白引起的致死性。双羟萘酸，一种苹果酸酶抑制剂，抑制突变核纤层蛋白引起的致死性。
Mutations in the human LMNA gene cause a collection of diseases called laminopathies, which includes muscular dystrophy and dilated cardiomyopathy. The LMNA gene encodes lamins, filamentous proteins that form a meshwork on the inner side of the nuclear envelope. How mutant lamins cause muscle disease is not well understood, and treatment options are currently limited. To understand the pathological functions of mutant lamins so that therapies can be developed, we generated new Drosophila models and human iPS cell-derived cardiomyocytes. In the Drosophila models, muscle-specific expression of the mutant lamins caused nuclear envelope defects, cytoplasmic protein aggregation, activation of the Nrf2/Keap1 redox pathway, and reductive stress. These defects reduced larval motility and caused death at the pupal stage. Patient-derived cardiomyocytes expressing mutant lamins showed nuclear envelope deformations. The Drosophila models allowed for genetic and pharmacological manipulations at the organismal level. Genetic interventions to increase autophagy, decrease Nrf2/Keap1 signaling, or lower reducing equivalents partially suppressed the lethality caused by mutant lamins. Moreover, treatment of flies with pamoic acid, a compound that inhibits the NADPH-producing malic enzyme, partially suppressed lethality. Taken together, these studies have identified multiple new factors as potential therapeutic targets for LMNA-associated muscular dystrophy. Drosophila models of LMNA muscular dystrophy exhibited redox imbalance. Amino acid substitutions in all three domains of lamins caused reductive stress. iPS cell-derived cardiomyocytes showed an altered response to NAC treatment. Genetic manipulation of autophagy regulators suppressed lethality caused by mutant lamins. Pamoic acid, a malic enzyme inhibitor, suppressed lethality caused by mutant lamins.
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影响因子：
10.6
作者：
Forman, Henry Jay;Zhang, Hongqiao;Rinna, Alessandra
通讯作者：
Rinna, Alessandra
影响因子：
13.3
作者：
Bartlett, Bryan J.;Isakson, Pauline;Finley, Kim D.
通讯作者：
Finley, Kim D.
DOI：
10.1042/bj20150568
发表时间：
2015-08-01
期刊：
The Biochemical journal
影响因子：
--
作者：
Dodson M;Redmann M;Rajasekaran NS;Darley-Usmar V;Zhang J
通讯作者：
Zhang J
影响因子：
5.3
作者：
Avila, A;Silverman, N;Moscat, J
通讯作者：
Moscat, J
DOI：
10.1007/978-1-4939-6371-3_2
发表时间：
2016-01-01
期刊：
DROSOPHILA: METHODS AND PROTOCOLS, 2ND EDITION
影响因子：
--
作者：
Caygill, Elizabeth E.;Brand, Andrea H.
通讯作者：
Brand, Andrea H.