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Costameric Integrin and Sarcoglycan protein levels are altered in a Drosophila model for Limb Girdle Muscular Dystrophy type 2H
Molecular Biology of the Cell ( IF 3.3 ) Pub Date : 2020-12-09 , DOI: 10.1091/mbc.e20-07-0453
Simranjot Bawa 1 , Samantha Gameros 1 , Kenny Baumann 2 , David S Brooks 1 , Joseph A Kollhoff 1 , Michal Zolkiewski 1 , Andrea David Re Cecconi 3 , Nicolò Panini 4 , Massimo Russo 4 , Rosanna Piccirillo 3 , David K Johnson 5 , Maithri M Kashipathy 6 , Kevin P Battaile 7 , Scott Lovell 6 , Samuel E A Bouyain 2 , Jessica Kawakami 2 , Erika R Geisbrecht 1, 2
Affiliation  

Mutations in two different domains of the ubiquitously expressed TRIM32 protein give rise to two clinically separate diseases, one of which is Limb-girdle muscular dystrophy type 2H (LGMD2H). Uncovering the muscle-specific role of TRIM32 in LGMD2H pathogenesis has proven difficult as neurogenic phenotypes, independent of LGMD2H pathology, are present in TRIM32 KO mice. We previously established a platform to study LGMD2H pathogenesis using Drosophila melanogaster as a model. Here we show that LGMD2H disease-causing mutations in the NHL domain are molecularly and structurally conserved between fly and human TRIM32. Furthermore, transgenic expression of a subset of myopathic alleles (R394H, D487N and 520fs) induce myofibril abnormalities, altered nuclear morphology and reduced TRIM32 protein levels, mimicking phenotypes in patients afflicted with LGMD2H. Intriguingly, we also report for the first time that the protein levels of βPS integrin and Sarcoglycan δ, both core components of costameres, are elevated in TRIM32 disease-causing alleles. Similarly, murine myoblasts overexpressing a catalytically inactive TRIM32 mutant, aberrantly accumulate α- and β-Dystroglycan and α-Sarcoglycan. We speculate that the stoichiometric loss of costamere components disrupts costamere complexes to promote muscle degeneration.



中文翻译:

在 2H 型肢带型肌营养不良症的果蝇模型中,Costameric Integrin 和 Sarcoglycan 蛋白水平发生了改变

无处不在表达的 TRIM32 蛋白的两个不同结构域中的突变会导致两种临床上独立的疾病,其中一种是 2H 型肢带型肌营养不良症 (LGMD2H)。发现 TRIM32 在 LGMD2H 发病机制中的肌肉特异性作用已被证明是困难的,因为与 LGMD2H 病理无关的神经源性表型存在于TRIM32 KO小鼠中。我们之前建立了一个使用黑腹果蝇研究 LGMD2H 发病机制的平台作为模特。在这里,我们表明 NHL 域中的 LGMD2H 致病突变在果蝇和人类 TRIM32 之间在分子和结构上是保守的。此外,肌病等位基因子集(R394H、D487N 和 520fs)的转基因表达可诱导肌原纤维异常、核形态改变和 TRIM32 蛋白水平降低,模拟 LGMD2H 患者的表型。有趣的是,我们还首次报告了在 TRIM32 致病等位基因中,βPS 整合素和肌聚糖 δ 的蛋白质水平升高,这两者都是肋骨的核心成分。类似地,过度表达无催化活性的 TRIM32 突变体的鼠成肌细胞异常积累 α- 和 β-肌聚糖和α-肌聚糖。

更新日期:2020-12-09
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