Activation of the Unfolded Protein Response in Sporadic Inclusion-Body Myositis but Not in Hereditary GNE Inclusion-Body Myopathy.
Activation of the Unfolded Protein Response in Sporadic Inclusion-Body Myositis but Not in Hereditary GNE Inclusion-Body Myopathy.
复制标题
DOI：
10.1097/nen.0000000000000196
复制
发表时间：
2015-06
影响因子：
3.2
通讯作者：
Askanas V
中科院分区：
文献类型：
--
作者：
Nogalska A;D'Agostino C;Engel WK;Cacciottolo M;Asada S;Mori K;Askanas V
散发性包涵体肌炎（s-IBM）是最常见的年龄相关性肌病，其患者的肌纤维以自噬空泡和含有淀粉样蛋白-β和磷酸化tau的泛素化和嗜酸性多蛋白聚集体的积累为特征。由于GNE突变（GNE-h-IBM）引起的常染色体隐性遗传性包涵体肌病的肌纤维显示出相似的病理特征，除了不太明显的嗜中性粒细胞。未折叠/错误折叠蛋白在内质网腔内的积累导致内质网应激，这使得未折叠蛋白反应（UPR）成为一种保护机制。在这里，我们首次证明UPR在s-IBM肌肉活检中被激活，因为a）ATF 4蛋白增加，其靶点CHOP的mRNA增加，B）ATF 6切割，其靶点GRP 78的mRNA增加，以及c）XBP-1的剪接形式增加，EDEM的mRNA增加，EDEM是切割的ATF 6和剪接的XBP-1的异二聚体的靶点。与此相反，我们没有发现类似的证据的UPR诱导在GNE-h-IBM患者肌肉，这表明不同的细胞内机制可能导致相似的病理表型。有趣的是，培养的GNE-h-IBM肌纤维对实验性ER应激刺激有强烈的UPR反应，这表明GNE突变本身并不导致GNE-h-IBM活检肌肉中UPR的缺乏。
Muscle fibers in patients with sporadic inclusion-body myositis (s-IBM), the most common age-associated myopathy, are characterized by autophagic vacuoles and accumulation of ubiquitinated and congophilic multiprotein aggregates that contain amyloid-β and phosphorylated tau. Muscle fibers of autosomal-recessive hereditary inclusion-body myopathy due to the GNE mutation (GNE-h-IBM) display similar pathologic features, except with less pronounced congophilia. Accumulation of unfolded/misfolded proteins inside the ER lumen leads to ER stress, which elicits the unfolded protein response (UPR) as a protective mechanism. Here we demonstrate for the first time that UPR is activated in s-IBM muscle biopsies, since there was a) increased ATF4 protein and increased mRNA of its target CHOP, b) cleavage of the ATF6 and increased mRNA of its target GRP78, and c) an increase of the spliced form of XBP-1 and increased mRNA of EDEM, target of heterodimer of cleaved ATF6 and spliced XBP-1. In contrast, we did not find similar evidence of the UPR induction in GNE-h-IBM patient muscle, suggesting that different intracellular mechanisms might lead to the similar pathological phenotypes. Interestingly, cultured GNE-h-IBM muscle fibers had a robust UPR response to experimental ER stress stimuli, suggesting that the GNE mutation per se is not responsible for the lack of UPR in GNE-h-IBM biopsied muscle.