肌萎缩侧索硬化症中的突变 FUS 和 ELAVL4（HuD）异常串扰。

Mutant FUS and ELAVL4 (HuD) Aberrant Crosstalk in Amyotrophic Lateral Sclerosis.

机构信息

Center for Life Nano Science, Istituto Italiano di Tecnologia, Viale Regina Elena 291, 00161 Rome, Italy; Department of Biology and Biotechnology Charles Darwin, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.

Department of Biology and Biotechnology Charles Darwin, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.

出版信息

Cell Rep. 2019 Jun 25;27(13):3818-3831.e5. doi: 10.1016/j.celrep.2019.05.085.

Amyotrophic lateral sclerosis (ALS) has been genetically linked to mutations in RNA-binding proteins (RBPs), including FUS. Here, we report the RNA interactome of wild-type and mutant FUS in human motor neurons (MNs). This analysis identified a number of RNA targets. Whereas the wild-type protein preferentially binds introns, the ALS mutation causes a shift toward 3' UTRs. Neural ELAV-like RBPs are among mutant FUS targets. As a result, ELAVL4 protein levels are increased in mutant MNs. ELAVL4 and mutant FUS interact and co-localize in cytoplasmic speckles with altered biomechanical properties. Upon oxidative stress, ELAVL4 and mutant FUS are engaged in stress granules. In the spinal cord of FUS ALS patients, ELAVL4 represents a neural-specific component of FUS-positive cytoplasmic aggregates, whereas in sporadic patients it co-localizes with phosphorylated TDP-43-positive inclusions. We propose that pathological mutations in FUS trigger an aberrant crosstalk with ELAVL4 with implications for ALS.

肌萎缩侧索硬化症（ALS）已被证实与 RNA 结合蛋白（RBPs）的基因突变有关，其中包括 FUS。在这里，我们报告了野生型和突变型 FUS 在人类运动神经元（MNs）中的 RNA 相互作用组。该分析确定了许多 RNA 靶标。野生型蛋白优先结合内含子，而 ALS 突变则导致其向 3'UTR 转移。神经 ELAV 样 RBPs 是突变型 FUS 的靶标之一。结果，突变型 MNs 中的 ELAVL4 蛋白水平增加。ELAVL4 和突变型 FUS 相互作用，并在细胞质斑点中共定位，这些斑点具有改变的生物力学特性。在氧化应激下，ELAVL4 和突变型 FUS 参与应激颗粒。在 FUS ALS 患者的脊髓中，ELAVL4 是 FUS 阳性细胞质聚集体中神经特异性成分，而在散发性患者中，它与磷酸化 TDP-43 阳性包含物共定位。我们提出，FUS 的病理性突变引发了与 ELAVL4 的异常串扰，这对 ALS 有影响。