Distinct partitioning of ALS associated TDP-43, FUS and SOD1 mutants into cellular inclusions
Distinct partitioning of ALS associated TDP-43, FUS and SOD1 mutants into cellular inclusions
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DOI：
10.1038/srep13416
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发表时间：
2015-08-21
影响因子：
4.6
通讯作者：
Yerbury, Justin J.
中科院分区：
文献类型：
--
作者：
Farrawell, Natalie E.;Lambert-Smith, Isabella A.;Yerbury, Justin J.
肌萎缩侧索硬化症是一种进展迅速的神经退行性疾病，与蛋白质错误折叠和聚集有关。大多数病例以TDP-43阳性包涵体为特征，而少数家族性ALS病例分别为FUS和SOD 1阳性。细胞可以产生可变类型的内含物，包括先前表征的侵袭体、IPOD或JUNQ结构，这取决于错误折叠的蛋白质。SOD 1总是形成JUNQ包涵体，但仍不清楚其他ALS蛋白聚集体是否作为这些先前描述的包涵体类型之一出现或形成独特的结构。在这里，我们表明，FUS蛋白质分配到IPOD，JUNQ或替代结构，包含一个移动的部分，不依赖微管，最初不包含泛素。TDP-43包涵体以微管独立的方式形成，不含移动的部分，但与JUNQ包涵体和另一种交替结构共定位。我们的结论是，RNA结合蛋白TDP-43和FUS并不始终符合目前表征的包涵体模型，这表明细胞具有比目前认为的更大的生成包涵体的库，并暗示ALS中的毒性并不源于特定的聚集过程或聚集结构。
Amyotrophic lateral sclerosis is a rapidly progressing neurodegenerative disease associated with protein misfolding and aggregation. Most cases are characterized by TDP-43 positive inclusions, while a minority of familial ALS cases are instead FUS and SOD1 positive respectively. Cells can generate inclusions of variable type including previously characterized aggresomes, IPOD or JUNQ structures depending on the misfolded protein. SOD1 invariably forms JUNQ inclusions but it remains unclear whether other ALS protein aggregates arise as one of these previously described inclusion types or form unique structures. Here we show that FUS variably partitioned to IPOD, JUNQ or alternate structures, contain a mobile fraction, were not microtubule dependent and initially did not contain ubiquitin. TDP-43 inclusions formed in a microtubule independent manner, did not contain a mobile fraction but variably colocalized to JUNQ inclusions and another alternate structure. We conclude that the RNA binding proteins TDP-43 and FUS do not consistently fit the currently characterised inclusion models suggesting that cells have a larger repertoire for generating inclusions than currently thought, and imply that toxicity in ALS does not stem from a particular aggregation process or aggregate structure.