Widespread RNA metabolism impairment in sporadic inclusion body myositis TDP43-proteinopathy.
Widespread RNA metabolism impairment in sporadic inclusion body myositis TDP43-proteinopathy.
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DOI：
10.1016/j.neurobiolaging.2013.12.029
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发表时间：
2014-06
影响因子：
4.2
通讯作者：
Fratta P
中科院分区：
文献类型：
--
作者：
Cortese A;Plagnol V;Brady S;Simone R;Lashley T;Acevedo-Arozena A;de Silva R;Greensmith L;Holton J;Hanna MG;Fisher EM;Fratta P
TDP43蛋白错位是神经退行性疾病肌萎缩性侧索硬化症和额颞叶痴呆的标志，编码TDP43的基因突变导致这两种疾病，进一步突出了其在疾病发病机制中的作用。TDP43是一种异质核糖核蛋白，因此提示RNA代谢的改变在这些疾病中起作用，尽管缺乏患者的直接证据。散发性包涵体肌炎（sIBM）是最常见的获得性肌病，发生在50岁以上的成年人中，TDP43的异常细胞质积累在sIBM肌纤维中一直被描述。在这里，我们从冷冻的sIBM肌肉活检中提取高质量的RNA，用于tdp43蛋白病患者组织的转录组学研究。令人惊讶的是，我们在RNA代谢途径中发现了广泛的sibm特异性变化。与这一发现一致，我们描述了新的RNA结合蛋白在sIBM肌纤维的细胞质中错定位和MAPT的剪接变化，MAPT是一个先前被证明在sIBM中起作用的基因。我们的数据表明，RNA代谢的广泛改变是sIBM疾病发病机制的一个新方面。这些发现还证明，在tdp43蛋白病变患者中，异质性核糖核蛋白病理与RNA代谢改变之间存在关联，并对神经退行性疾病（如肌萎缩性侧索硬化症和额颞叶痴呆）具有重要意义。
TDP43 protein mislocalization is a hallmark of the neurodegenerative diseases amyotrophic lateral sclerosis and frontotemporal dementia, and mutations in the gene encoding TDP43 cause both disorders, further highlighting its role in disease pathogenesis. TDP43 is a heterogenous ribonucleoprotein, therefore suggesting that alterations in RNA metabolism play a role in these disorders, although direct evidence in patients is lacking. Sporadic inclusion body myositis (sIBM) is the most common acquired myopathy occurring in adults aged older than 50 years and abnormal cytoplasmic accumulations of TDP43 have been consistently described in sIBM myofibers. Here, we exploit high quality RNA from frozen sIBM muscle biopsies for transcriptomic studies on TDP43-proteinopathy patient tissue. Surprisingly, we found widespread sIBM-specific changes in the RNA metabolism pathways themselves. Consistent with this finding, we describe novel RNA binding proteins to mislocalize in the cytoplasm of sIBM myofibers and splicing changes in MAPT, a gene previously shown to play a role in sIBM. Our data indicate widespread alterations of RNA metabolism are a novel aspect of disease pathogenesis in sIBM. These findings also document an association, in TDP43-proteinopathy patients, between heterogenous ribonucleoprotein pathology and RNA metabolism alterations and carry importance for neurodegenerative diseases, such as amyotrophic lateral sclerosis and frontotemporal dementia.
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影响因子：
9.9
作者：
Engel, WK;Askanas, V
通讯作者：
Askanas, V
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y
影响因子：
34.7
作者：
Lee, Edward B.;Lee, Virginia M-Y;Trojanowski, John Q.
通讯作者：
Trojanowski, John Q.
影响因子：
4.8
作者：
Buratti, E;Brindisi, A;Baralle, FE
通讯作者：
Baralle, FE
DOI：
10.1016/j.bbadis.2005.12.003
发表时间：
2006-04-01
影响因子：
6.2
作者：
Leroy, O;Wang, JN;Caillet-Boudin, ML
通讯作者：
Caillet-Boudin, ML