FUS Interacts with HSP60 to Promote Mitochondrial Damage.
FUS Interacts with HSP60 to Promote Mitochondrial Damage.
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DOI：
10.1371/journal.pgen.1005357
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发表时间：
2015-09
期刊：
影响因子：
4.5
通讯作者：
Wu JY
中科院分区：
文献类型：
--
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
FUS蛋白病是一组异质性疾病，包括ALS-FUS和FTLD-FUS，其特征在于在受影响的患者中形成含有核蛋白FUS的包涵体。然而，潜在的分子和细胞缺陷仍不清楚。在这里，我们提供的线粒体定位的FUS和它的诱导线粒体损伤的证据。值得注意的是，FTLD-FUS脑样品显示FUS表达增加和线粒体缺陷。生物化学和遗传学数据表明，FUS与线粒体伴侣蛋白HSP 60相互作用，并且FUS易位至线粒体至少部分地由HSP 60介导。下调HSP 60可减少转基因果蝇中FUS表达引起的脑内FUS并部分挽救线粒体缺陷和神经退行性表型。这是第一个报告的直接线粒体靶向核蛋白与神经退行性疾病，这表明线粒体损伤可能代表了一个关键事件，在不同形式的FUS蛋白病和ALS-FUS和FTLD-FUS的共同病理特征。我们的研究为不同形式的FUS蛋白病的高度异质性和复杂的遗传表现提供了一个潜在的解释。我们的数据还表明，线粒体损伤可能是未来开发FUS蛋白病（一组破坏性神经退行性疾病）诊断和治疗工具的目标。肌萎缩侧索硬化症（ALS）和额颞叶变性（FTLD）是两组常见的和毁灭性的神经退行性疾病，其特征在于选定的神经元组的损失。FUS基因的突变与ALS相关，而在ALS和FTLD患者中均发现了含有FUS蛋白的包涵体。然而，FUS在这些疾病中的潜在致病机制仍不清楚。在这里，我们证明了野生型或ALS相关的突变FUS可以与线粒体伴侣蛋白HSP 60相互作用，HSP 60介导FUS定位到线粒体，导致线粒体损伤。线粒体损伤可能是FUS蛋白病的早期事件，并代表治疗这些致命疾病的潜在治疗靶点。
FUS-proteinopathies, a group of heterogeneous disorders including ALS-FUS and FTLD-FUS, are characterized by the formation of inclusion bodies containing the nuclear protein FUS in the affected patients. However, the underlying molecular and cellular defects remain unclear. Here we provide evidence for mitochondrial localization of FUS and its induction of mitochondrial damage. Remarkably, FTLD-FUS brain samples show increased FUS expression and mitochondrial defects. Biochemical and genetic data demonstrate that FUS interacts with a mitochondrial chaperonin, HSP60, and that FUS translocation to mitochondria is, at least in part, mediated by HSP60. Down-regulating HSP60 reduces mitochondrially localized FUS and partially rescues mitochondrial defects and neurodegenerative phenotypes caused by FUS expression in transgenic flies. This is the first report of direct mitochondrial targeting by a nuclear protein associated with neurodegeneration, suggesting that mitochondrial impairment may represent a critical event in different forms of FUS-proteinopathies and a common pathological feature for both ALS-FUS and FTLD-FUS. Our study offers a potential explanation for the highly heterogeneous nature and complex genetic presentation of different forms of FUS-proteinopathies. Our data also suggest that mitochondrial damage may be a target in future development of diagnostic and therapeutic tools for FUS-proteinopathies, a group of devastating neurodegenerative diseases. Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are two groups of common and devastating neurodegenerative diseases, characterized by losses of selected groups of neurons. Mutations in the FUS gene have been associated with ALS, whereas inclusion bodies containing the FUS protein have been discovered in both ALS and FTLD patients. However, the underlying pathogenic mechanisms of FUS in these diseases remain unclear. Here, we demonstrate that wild-type or ALS-associated mutant FUS can interact with mitochondrial chaperonin HSP60 and that HSP60 mediates FUS localization to mitochondria, leading to mitochondrial damage. Mitochondrial impairment may be an early event in FUS proteinopathies and represent a potential therapeutic target for treating these fatal diseases.