Brigham and Women's Hospital, Department of Neurology, Harvard Medical School, Boston, MA, USA.
Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
Neuromuscul Disord. 2014 Jul;24(7):611-6. doi: 10.1016/j.nmd.2014.04.012. Epub 2014 May 6.
Previous histopathologic studies of sporadic inclusion body myositis (sIBM) identified sarcoplasmic aggregation and myonuclear depletion of the predominantly nuclear heterogeneous nuclear ribonucleoprotein (hnRNP) TDP-43 in sIBM myofibers. Here, we examined sIBM muscle for abnormalities in two other hnRNPs hnRNPA1 and hnRNPA2B1, mutations in which cause multisystem proteinopathy associated with rimmed-vacuolar myopathies. Muscle biopsy specimens from 13 patients with sIBM and 13 patients without sIBM (dermatomyositis N=3, polymyositis N=3, muscular dystrophy N=3, motor neuron disease N=2, non-neuromuscular disease N=2) underwent immunohistochemistry for hnRNPA1, hnRNPA2B1, and TDP-43. Muscle transcriptional microarray data from 27 patients with sIBM and 12 patients without neuromuscular disease was analyzed. Depletion of hnRNPA1 and hnRNPA2B1 was present in 15% and 7% of sIBM myonuclei, respectively, compared with 1% and 0% of myonuclei in non-sIBM muscle. Sarcoplasmic aggregates of hnRNPA1 and hnRNPA2B1 distinct from TDP-43 aggregates were also found in sIBM. hnRNPA1 and hnRNPA2B1, as well as other hnRNPs, gene expression was unaltered in sIBM compared to normal muscle. Along with TDP-43, other hnRNPs, including hnRNPA1 and hnRNPA2B1, are depleted from sIBM myonuclei at the protein but not transcript level. The depletion of multiple hnRNPs from sIBM myonuclei together with their sarcoplasmic aggregation suggests that one aspect of sIBM pathophysiology may involve abnormal RNA metabolism that includes hyperassembly of ribonucleoprotein granules mediated by prion-like domains in hnRNPs, evolving into pathological aggregates.
先前对散发性包涵体肌炎（sIBM）的组织病理学研究发现，sIBM 肌纤维中存在核异质性核核糖核蛋白（hnRNP）TDP-43 的肌浆聚集和核内耗竭。在这里，我们研究了另外两种 hnRNPs hnRNPA1 和 hnRNPA2B1 在 sIBM 肌肉中的异常，这两种 hnRNPs 的突变会导致伴有边缘空泡肌病的多系统蛋白病。对 13 例 sIBM 患者和 13 例非 sIBM 患者（皮肌炎 N=3、多发性肌炎 N=3、肌营养不良症 N=3、运动神经元病 N=2、非神经肌肉疾病 N=2）的肌肉活检标本进行了 hnRNPA1、hnRNPA2B1 和 TDP-43 的免疫组织化学检查。分析了 27 例 sIBM 患者和 12 例非神经肌肉疾病患者的肌肉转录微阵列数据。与非 sIBM 肌肉中的 1%和 0%的肌核相比，hnRNPA1 和 hnRNPA2B1 的分别有 15%和 7%的 sIBM 肌核耗竭。在 sIBM 中还发现了与 TDP-43 聚集物不同的 hnRNPA1 和 hnRNPA2B1 的肌浆聚集物。与正常肌肉相比，sIBM 中的 hnRNPA1 和 hnRNPA2B1 以及其他 hnRNPs 的基因表达没有改变。与 TDP-43 一样，其他 hnRNPs，包括 hnRNPA1 和 hnRNPA2B1，在 sIBM 肌核中从蛋白质水平而不是转录水平耗竭。sIBM 肌核中多种 hnRNPs 的耗竭及其肌浆聚集表明，sIBM 病理生理学的一个方面可能涉及异常的 RNA 代谢，包括由 hnRNPs 的类 PrP 结构域介导的核糖核蛋白颗粒的过度组装，进而发展为病理性聚集物。
