Identification of a novel interaction of FUS and syntaphilin may explain synaptic and mitochondrial abnormalities caused by ALS mutations.
Identification of a novel interaction of FUS and syntaphilin may explain synaptic and mitochondrial abnormalities caused by ALS mutations.
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DOI：
10.1038/s41598-021-93189-6
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发表时间：
2021-06-30
影响因子：
4.6
通讯作者：
Vance C
中科院分区：
文献类型：
--
作者：
Salam S;Tacconelli S;Smith BN;Mitchell JC;Glennon E;Nikolaou N;Houart C;Vance C
肉瘤融合蛋白（FUS）异常表达是FUS相关性肌萎缩侧索硬化（ALS）和额颞叶痴呆（FTD）的标志。野生型FUS定位于突触并与线粒体蛋白相互作用，而突变已显示引起影响线粒体、突触和神经肌肉接头（NMJ）的病理变化。这表明FUS在调节突触和线粒体功能中的重要生理作用，目前尚不清楚。在本文中，我们提供的证据表明，错位的细胞质FUS引起线粒体和突触的变化，FUS在维持神经元的健康在体外和体内起着至关重要的作用。过表达突变FUS改变了原代神经元和斑马鱼模型中的突触数量和神经元复杂性。FUS被错误定位的程度导致突触变化的差异，这反映了线粒体数量和运输的变化。此外，我们发现FUS与线粒体系留蛋白Syntaphilin（SNPH）共定位，并且FUS中的突变影响这种关系。最后，我们证明突变FUS导致全局蛋白质翻译的变化。FUS和SNPH之间的这种定位可以解释观察到的导致全局蛋白质翻译缺陷的突触和线粒体缺陷。重要的是，我们的研究结果支持了FUS相关ALS疾病发病机制的“功能获得”假说。
Aberrantly expressed fused in sarcoma (FUS) is a hallmark of FUS-related amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Wildtype FUS localises to synapses and interacts with mitochondrial proteins while mutations have been shown to cause to pathological changes affecting mitochondria, synapses and the neuromuscular junction (NMJ). This indicates a crucial physiological role for FUS in regulating synaptic and mitochondrial function that is currently poorly understood. In this paper we provide evidence that mislocalised cytoplasmic FUS causes mitochondrial and synaptic changes and that FUS plays a vital role in maintaining neuronal health in vitro and in vivo. Overexpressing mutant FUS altered synaptic numbers and neuronal complexity in both primary neurons and zebrafish models. The degree to which FUS was mislocalised led to differences in the synaptic changes which was mirrored by changes in mitochondrial numbers and transport. Furthermore, we showed that FUS co-localises with the mitochondrial tethering protein Syntaphilin (SNPH), and that mutations in FUS affect this relationship. Finally, we demonstrated mutant FUS led to changes in global protein translation. This localisation between FUS and SNPH could explain the synaptic and mitochondrial defects observed leading to global protein translation defects. Importantly, our results support the ‘gain-of-function’ hypothesis for disease pathogenesis in FUS-related ALS.
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影响因子：
4.5
作者：
Deng J;Yang M;Chen Y;Chen X;Liu J;Sun S;Cheng H;Li Y;Bigio EH;Mesulam M;Xu Q;Du S;Fushimi K;Zhu L;Wu JY
通讯作者：
Wu JY
影响因子：
56.9
作者：
Kwiatkowski, T. J., Jr.;Bosco, D. A.;Brown, R. H., Jr.
通讯作者：
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影响因子：
14.5
作者：
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通讯作者：
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影响因子：
3.5
作者：
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通讯作者：
Drapeau, Pierre
线粒体受损在ALS小鼠的神经肌肉连接处的神经上发挥作用。
影响因子：
4.3
作者：
Rogers RS;Tungtur S;Tanaka T;Nadeau LL;Badawi Y;Wang H;Ni HM;Ding WX;Nishimune H
通讯作者：
Nishimune H