FUS toxicity is rescued by the modulation of lncRNA hsrω expression in Drosophila melanogaster.
FUS toxicity is rescued by the modulation of lncRNA hsrω expression in Drosophila melanogaster.
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DOI：
10.1038/s41598-017-15944-y
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发表时间：
2017-11-15
影响因子：
4.6
通讯作者：
Yamaguchi M
中科院分区：
文献类型：
--
作者：
Lo Piccolo L;Jantrapirom S;Nagai Y;Yamaguchi M
FUS是一种易聚集的hnRNP，参与转录和转录后调控，在一系列归类为FUS蛋白病的神经系统疾病中异常形成免疫反应性包涵体。虽然FUS已被广泛研究，这些疾病的潜在分子机制尚未得到详细阐明。我们以前报道过lncRNA hsrω的RNAi改变了果蝇FUS在果蝇中枢神经系统中的表达和亚细胞定位。为了更清楚地了解hsrω在FUS毒性中的作用，我们在此用和不用hsrω RNAi背景驱动果蝇眼睛中人FUS的表达。我们发现hFUS在很大程度上是可溶的，并且也能够形成聚集体。因此，hFUS是有毒的，诱导异常的眼睛形态学和色素沉着的丧失。hsrω双链RNA的共表达降低了hFUS的转录水平，并诱导了细胞质中无毒的hFUS-LAMP 1不溶性包涵体的形成。这些事件的组合导致hFUS摩尔过量的滴定和hFUS聚集体的去除以挽救毒性。这些结果揭示了参与易聚集的hnRNP的管理的lncRNA依赖性途径的存在，表明适当形成的FUS包涵体对细胞无毒。
FUS is an aggregation-prone hnRNP involved in transcriptional and post-transcriptional regulation that aberrantly forms immunoreactive inclusion bodies in a range of neurological diseases classified as FUS-proteinopathies. Although FUS has been extensively examined, the underlying molecular mechanisms of these diseases have not yet been elucidated in detail. We previously reported that RNAi of the lncRNA hsrω altered the expression and sub-cellular localization of Drosophila FUS in the central nervous system of the fly. In order to obtain a clearer understanding of the role of hsrω in FUS toxicity, we herein drove the expression of human FUS in Drosophila eyes with and without a hsrω RNAi background. We found that hFUS was largely soluble and also able to form aggregates. As such, hFUS was toxic, inducing an aberrant eye morphology with the loss of pigmentation. The co-expression of hsrω double-stranded RNA reduced hFUS transcript levels and induced the formation of cytoplasmic non-toxic hFUS-LAMP1-insoluble inclusions. The combination of these events caused the titration of hFUS molar excess and a removal of hFUS aggregates to rescue toxicity. These results revealed the presence of a lncRNA-dependent pathway involved in the management of aggregation-prone hnRNPs, suggesting that properly formed FUS inclusions are not toxic to cells.
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影响因子：
4.5
作者：
Kang X;Li W;Zhou Y;Ni M
通讯作者：
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通讯作者：
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