Genetic interaction of hnRNPA2B1 and DNAJB6 in a Drosophila model of multisystem proteinopathy.
Genetic interaction of hnRNPA2B1 and DNAJB6 in a Drosophila model of multisystem proteinopathy.
复制标题
多系统蛋白病果蝇模型中 hnRNPA2B1 和 DNAJB6 的遗传相互作用。
DOI：
10.1093/hmg/ddv627
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发表时间：
2016
期刊：
影响因子：
--
通讯作者：
Kim HJ.
中科院分区：
文献类型：
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作者：
Li S;Zhang P;Freibaum BD;Kim NC;Kolaitis RM;Molliex A;Kanagaraj AP;Yabe I;Tanino M;Tanaka S;Sasaki H;Ross ED;Taylor JP;Kim HJ.
成人发病的遗传性肌病具有相似的病理特征，包括遗传性包涵体肌病（hIBM）和肢带型肌营养不良症（LGMD），是一组遗传异质性的肌肉疾病。目前尚不清楚这些遗传性肌病是否由不同类型的基因突变引起的病因相关。在这里，我们利用一个遗传模型系统来建立两个不同基因hnRNPA 2B 1和DNAJB 6突变引起的疾病之间的机制联系。hrb 98 DE和mrj分别是人RNPA 2B 1和DNAJB 6的果蝇同源物。我们将疾病同源突变引入Hrb 98 DE，从而在遗传学上易于处理的模型系统中捕获突变依赖的表型。hnRNPA 2B 1或Hrb 98 DE的疾病相关突变形式在苍蝇肌肉中的异位表达导致了进行性的、年龄依赖性的细胞质包涵体病理学，正如在患有hnRNPA 2B 1相关肌病的人类中所观察到的那样。细胞质内含物由hnRNPA 2B 1或Hrb 98 DE蛋白与应激颗粒标记物ROX 8和额外的内源性RNA结合蛋白（RBP）组成，表明这些病理性内含物与应激颗粒有关。值得注意的是，TDP-43也被募集到这些细胞质内含物中。值得注意的是，MRJ的过度表达挽救了这种表型，并抑制了细胞质内含物的形成，而减少内源性MRJ的一个经典的功能丧失等位基因增强it. Further，野生型，但不疾病相关的，突变形式的MRJ相互作用的RBPs热休克后，并防止其聚集。这些结果表明疾病相关的RBP和DNAJB 6/mrj之间的遗传和物理相互作用，提示hIBM和LGMD的发病机制之间的病因重叠，由hnRNPA 2B 1和DNAJB 6的突变启动。
Adult-onset inherited myopathies with similar pathological features, including hereditary inclusion body myopathy (hIBM) and limb-girdle muscular dystrophy (LGMD), are a genetically heterogeneous group of muscle diseases. It is unclear whether these inherited myopathies initiated by mutations in distinct classes of genes are etiologically related. Here, we exploit a genetic model system to establish a mechanistic link between diseases caused by mutations in two distinct genes,hnRNPA2B1andDNAJB6. Hrb98DEandmrjare theDrosophila melanogasterhomologs of humanhnRNPA2B1andDNAJB6, respectively. We introduced disease-homologous mutations toHrb98DE, thus capturing mutation-dependent phenotypes in a genetically tractable model system. Ectopic expression of the disease-associated mutant form of hnRNPA2B1 or Hrb98DE in fly muscle resulted in progressive, age-dependent cytoplasmic inclusion pathology, as observed in humans withhnRNPA2B1-related myopathy. Cytoplasmic inclusions consisted of hnRNPA2B1 or Hrb98DE protein in association with the stress granule marker ROX8 and additional endogenous RNA-binding proteins (RBPs), suggesting that these pathological inclusions are related to stress granules. Notably, TDP-43 was also recruited to these cytoplasmic inclusions. Remarkably, overexpression of MRJ rescued this phenotype and suppressed the formation of cytoplasmic inclusions, whereas reduction of endogenous MRJ by a classical loss of function allele enhanced it. Moreover, wild-type, but not disease-associated, mutant forms of MRJ interacted with RBPs after heat shock and prevented their accumulation in aggregates. These results indicate both genetic and physical interactions between disease-linked RBPs andDNAJB6/mrj, suggesting etiologic overlap between the pathogenesis of hIBM and LGMD initiated by mutations inhnRNPA2B1andDNAJB6.