Low molecular weight species of TDP-43 generated by abnormal splicing form inclusions in amyotrophic lateral sclerosis and result in motor neuron death.
Low molecular weight species of TDP-43 generated by abnormal splicing form inclusions in amyotrophic lateral sclerosis and result in motor neuron death.
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DOI：
10.1007/s00401-015-1412-5
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发表时间：
2015-07
影响因子：
12.7
通讯作者：
Robertson J
中科院分区：
文献类型：
--
作者：
Xiao S;Sanelli T;Chiang H;Sun Y;Chakrabartty A;Keith J;Rogaeva E;Zinman L;Robertson J
在肌萎缩侧索硬化症(ALS)和额颞叶变性(FTLD)中，TDP-43蛋白病变的一个特征是存在包含TAR DNA结合蛋白43(TDP-43)C末端区域的低分子物种。在这里，我们已经确定了TDP-43的一个新的剪接变体，它在ALS中上调，并通过使用替代的翻译起始密码子(ATGMet85)产生一个35 kDa的N-末端截断物种，这里表示为Met85-TDP-35。在人神经母细胞瘤细胞中异位表达的Met85-TDP-35表现出较低的溶解度、胞浆分布和聚集。此外，Met85-TDP-35将全长TDP-43从细胞核中隔离，形成细胞质聚集体。Met85-TDP-35在原代运动神经元中的表达导致Met85-TDP-35阳性胞浆聚集体的形成和运动神经元的死亡。一种针对Met85-TDP-35的新表位抗体标记了ALS-FTLD病组织尿素可溶提取物的免疫印迹上的35 kDa低分子量物种，以及ALS脊髓切片中共标记的TDP-43阳性包涵体，证实了该物种的生理相关性。这些结果表明，ALS-FTLD中的35 kDa低分子量物种可能是由于异常剪接事件和下游起始密码子的使用而产生的，可能代表了TDP-43诱导其致病的机制。本文的在线版本(doi：10.1007/s00401-0151412-5)包含补充材料，授权用户可以使用。
The presence of lower molecular weight species comprising the C-terminal region of TAR DNA-binding protein 43 (TDP-43) is a characteristic of TDP-43 proteinopathy in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Here, we have identified a novel splice variant of TDP-43 that is upregulated in ALS and generates a 35-kDa N-terminally truncated species through use of an alternate translation initiation codon (ATGMet85), denoted here as Met85-TDP-35. Met85-TDP-35 expressed ectopically in human neuroblastoma cells exhibited reduced solubility, cytoplasmic distribution, and aggregation. Furthermore, Met85-TDP-35 sequestered full-length TDP-43 from the nucleus to form cytoplasmic aggregates. Expression of Met85-TDP-35 in primary motor neurons resulted in the formation of Met85-TDP-35-positive cytoplasmic aggregates and motor neuron death. A neo-epitope antibody specific for Met85-TDP-35 labeled the 35-kDa lower molecular weight species on immunoblots of urea-soluble extracts from ALS-FTLD disease-affected tissues and co-labeled TDP-43-positive inclusions in ALS spinal cord sections, confirming the physiological relevance of this species. These results show that the 35-kDa low molecular weight species in ALS-FTLD can be generated from an abnormal splicing event and use of a downstream initiation codon and may represent a mechanism by which TDP-43 elicits its pathogenicity. The online version of this article (doi:10.1007/s00401-015-1412-5) contains supplementary material, which is available to authorized users.
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影响因子：
7.8
作者：
Robertson, Janice;Doroudchi, Mohammad M;Nguyen, Minh Dang;Durham, Heather D;Strong, Michael J;Shaw, Gerry;Julien, Jean-Pierre;Mushynski, Walter E
通讯作者：
Mushynski, Walter E
影响因子：
25
作者：
Polymenidou, Magdalini;Lagier-Tourenne, Clotilde;Hutt, Kasey R.;Huelga, Stephanie C.;Moran, Jacqueline;Liang, Tiffany Y.;Ling, Shuo-Chien;Sun, Eveline;Wancewicz, Edward;Mazur, Curt;Kordasiewicz, Holly;Sedaghat, Yalda;Donohue, John Paul;Shiue, Lily;Bennett, C. Frank;Yeo, Gene W.;Cleveland, Don W.
通讯作者：
Cleveland, Don W.
影响因子：
5.3
作者：
Xiao, Shangxi;Tjostheim, Sonja;Robertson, Janice
通讯作者：
Robertson, Janice
影响因子：
--
作者：
Xi, Zhengrui;Zinman, Lorne;Grinberg, Yakov;Moreno, Danielle;Sato, Christine;Bilbao, Juan M.;Ghani, Mahdi;Hernandez, Isabel;Ruiz, Agustin;Boada, Merce;Moron, Francisco J.;Lang, Anthony E.;Marras, Connie;Bruni, Amalia;Colao, Rosanna;Maletta, Raffaele G.;Puccio, Gianfranco;Rainero, Innocenzo;Pinessi, Lorenzo;Galimberti, Daniela;Morrison, Karen E.;Moorby, Catriona;Stockton, Joanne D.;Masellis, Mario;Black, Sandra E.;Hazrati, Lili-Naz;Liang, Yan;de With, Jan van Haersma;Fornazzari, Luis;Villagra, Roque;Rojas-Garcia, Ricardo;Clarimon, Jordi;Mayeux, Richard;Robertson, Janice;St George-Hyslop, Peter;Rogaeva, Ekaterina
通讯作者：
Rogaeva, Ekaterina
影响因子：
12.7
作者：
Yokota O;Davidson Y;Bigio EH;Ishizu H;Terada S;Arai T;Hasegawa M;Akiyama H;Sikkink S;Pickering-Brown S;Mann DM
通讯作者：
Mann DM