Widespread FUS mislocalization is a molecular hallmark of amyotrophic lateral sclerosis
Widespread FUS mislocalization is a molecular hallmark of amyotrophic lateral sclerosis
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DOI：
10.1093/brain/awz217
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发表时间：
2019-09-01
期刊：
影响因子：
14.5
通讯作者：
Patani, Rickie
中科院分区：
文献类型：
--
作者：
Tyzack, Giulia E.;Luisier, Raphaelle;Patani, Rickie
导致肌萎缩侧索硬化症(ALS)的突变明显涉及普遍表达的、以核RNA结合蛋白为主的蛋白，在此背景下形成病理性的细胞质内含物。然而，野生型RNA结合蛋白错位而不一定成为细胞质内含物本身的成分的可能性仍然相对未被探索。我们推测，在非聚集状态下，肉瘤融合的RNA结合蛋白(FUS)的核到细胞质的错误定位可能在ALS中发生得比之前认为的更广泛。为了解决这一假设，我们分析了由VCP突变引起的人类ALS诱导多能干细胞模型中的运动神经元。此外，我们还检查了小鼠转基因模型和人类散发性ALS病例的死后组织。我们报告了在VCP突变相关的ALS中FUS的核到细胞质的错误定位，更重要的是，在多个病例的散发性ALS脊髓组织中。此外，我们提供的证据表明，FUS蛋白与SFPQ转录本中异常保留的内含子结合，该内含子从细胞核输出到细胞质中。总之，这些数据支持ALS发病机制的模型，在该模型中，SFPQ转录本中异常的内含子保留通过直接相互作用和核输出导致FUS错误定位。综上所述，我们报告了ALS中广泛存在的FUS蛋白的错误定位，并提出了这一过程的潜在机制。
Mutations causing amyotrophic lateral sclerosis (ALS) clearly implicate ubiquitously expressed and predominantly nuclear RNA binding proteins, which form pathological cytoplasmic inclusions in this context. However, the possibility that wild-type RNA binding proteins mislocalize without necessarily becoming constituents of cytoplasmic inclusions themselves remains relatively unexplored. We hypothesized that nuclear-to-cytoplasmic mislocalization of the RNA binding protein fused in sarcoma (FUS), in an unaggregated state, may occur more widely in ALS than previously recognized. To address this hypothesis, we analysed motor neurons from a human ALS induced-pluripotent stem cell model caused by the VCP mutation. Additionally, we examined mouse transgenic models and post-mortem tissue from human sporadic ALS cases. We report nuclear-to-cytoplasmic mislocalization of FUS in both VCP-mutation related ALS and, crucially, in sporadic ALS spinal cord tissue from multiple cases. Furthermore, we provide evidence that FUS protein binds to an aberrantly retained intron within the SFPQ transcript, which is exported from the nucleus into the cytoplasm. Collectively, these data support a model for ALS pathogenesis whereby aberrant intron retention in SFPQ transcripts contributes to FUS mislocalization through their direct interaction and nuclear export. In summary, we report widespread mislocalization of the FUS protein in ALS and propose a putative underlying mechanism for this process.