Cell environment shapes TDP-43 function with implications in neuronal and muscle disease.
Cell environment shapes TDP-43 function with implications in neuronal and muscle disease.
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DOI：
10.1038/s42003-022-03253-8
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发表时间：
2022-04-05
影响因子：
5.9
通讯作者：
Buratti E
中科院分区：
文献类型：
--
作者：
Šušnjar U;Škrabar N;Brown AL;Abbassi Y;Phatnani H;NYGC ALS Consortium;Cortese A;Cereda C;Bugiardini E;Cardani R;Meola G;Ripolone M;Moggio M;Romano M;Secrier M;Fratta P;Buratti E
TDP-43（TAR DNA结合蛋白43）聚集和重新分布被认为是肌萎缩侧索硬化症和额颞叶痴呆的标志。由于最近在包涵体肌炎患者的肌肉中描述了TDP-43包涵体，这突出了了解TDP-43在中枢神经系统之外的作用的需要。使用RNA-seq，我们直接比较了TDP-43介导的肌肉（C2 C12）和神经元（NSC 34）小鼠细胞中的RNA加工。TDP-43表现出靶向每种细胞类型中独特转录物的细胞类型特征行为，这是由于RNA结合蛋白的特征表达，其影响TDP-43的性能并定义细胞类型特异性剪接。在这两种细胞系中通常失调的剪接事件中，我们确定了一些在人类细胞中也依赖TDP-43的剪接事件。这些替代外显子的包含水平在患有FTLD和IBM的患者的组织中改变。因此，我们提出TDP-43功能障碍以共同或组织特异性方式促进疾病发展。TDP-43聚集的病因表现在肌肉和神经元细胞中。在这里，作者展示了TDP 43的细胞类型特征功能，反映在异常剪接中，可能有助于疾病的发展。
TDP-43 (TAR DNA-binding protein 43) aggregation and redistribution are recognised as a hallmark of amyotrophic lateral sclerosis and frontotemporal dementia. As TDP-43 inclusions have recently been described in the muscle of inclusion body myositis patients, this highlights the need to understand the role of TDP-43 beyond the central nervous system. Using RNA-seq, we directly compare TDP-43-mediated RNA processing in muscle (C2C12) and neuronal (NSC34) mouse cells. TDP-43 displays a cell-type-characteristic behaviour targeting unique transcripts in each cell-type, which is due to characteristic expression of RNA-binding proteins, that influence TDP-43’s performance and define cell-type specific splicing. Among splicing events commonly dysregulated in both cell lines, we identify some that are TDP-43-dependent also in human cells. Inclusion levels of these alternative exons are altered in tissues of patients suffering from FTLD and IBM. We therefore propose that TDP-43 dysfunction contributes to disease development either in a common or a tissue-specific manner. The aetiology of the TDP-43 aggregation manifest itself in the muscle and neuronal cells. Here authors show cell-type characteristic functions of TDP43, reflected in aberrant splicing, likely contributing to disease development.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
29
作者：
Barres, Romain;Yan, Jie;Zierath, Juleen R.
通讯作者：
Zierath, Juleen R.
影响因子：
10.5
作者：
Cabili, Moran N.;Trapnell, Cole;Rinn, John L.
通讯作者：
Rinn, John L.
影响因子：
4.8
作者：
Cascella, Roberta;Capitini, Claudia;Chiti, Fabrizio
通讯作者：
Chiti, Fabrizio
影响因子：
14.9
作者：
Appocher, Chiara;Mohagheghi, Fatemeh;Buratti, Emanuele
通讯作者：
Buratti, Emanuele