Compromised paraspeckle formation as a pathogenic factor in FUSopathies.
Compromised paraspeckle formation as a pathogenic factor in FUSopathies.
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DOI：
10.1093/hmg/ddt622
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发表时间：
2014-05-01
影响因子：
3.5
通讯作者：
Buchman VL
中科院分区：
文献类型：
--
作者：
Shelkovnikova TA;Robinson HK;Troakes C;Ninkina N;Buchman VL
Paraspeckles 是由一组特殊蛋白质在长非编码 RNA NEAT1 上组装而成的核体；它们在超编辑转录本的核保留中发挥作用，并与细胞应激反应相关。肉瘤融合蛋白 (FUS) 与许多神经退行性疾病有关，是副斑点的重要成分。我们已经证明，它招募到这些核结构是由 N 末端区域介导的，并且需要类似朊病毒的活性。 FUS 以 RNA 依赖性方式与副斑点的主要成分 p54nrb/NONO 相互作用，并以与其他副斑点蛋白相同的方式对细胞稳态的变化（例如转录速率或蛋白质甲基化水平的变化）做出反应。 FUS 还调节培养细胞中的 NEAT1 水平和副斑点形成，FUS 缺陷会导致副斑点丧失。病理性功能获得性 FUS 突变可能会影响人类疾病中的副斑点功能，因为错误定位的肌萎缩侧索硬化症 (ALS) 相关的 FUS 变异将其他副斑点蛋白隔离在培养细胞中形成的聚集体中，并隔离在 FUS 病转基因小鼠模型中的神经元包涵体中。此外，我们在由 FUS 突变引起的家族性 ALS 患者的运动神经元中检测到了大量的 p54nrb/NONO 阳性内含物，但在其他 ALS 病例中没有检测到。我们的结果表明，FUS 功能的丧失和获得都会引发旁斑组装的破坏，这可能会损害神经元的保护反应，从而导致 FUSo 病的发病机制。
Paraspeckles are nuclear bodies formed by a set of specialized proteins assembled on the long non-coding RNA NEAT1; they have a role in nuclear retention of hyperedited transcripts and are associated with response to cellular stress. Fused in sarcoma (FUS) protein, linked to a number of neurodegenerative disorders, is an essential paraspeckle component. We have shown that its recruitment to these nuclear structures is mediated by the N-terminal region and requires prion-like activity. FUS interacts with p54nrb/NONO, a major constituent of paraspeckles, in an RNA-dependent manner and responds in the same way as other paraspeckle proteins to alterations in cellular homeostasis such as changes in transcription rates or levels of protein methylation. FUS also regulates NEAT1 levels and paraspeckle formation in cultured cells, and FUS deficiency leads to loss of paraspeckles. Pathological gain-of-function FUS mutations might be expected to affect paraspeckle function in human diseases because mislocalized amyotrophic lateral sclerosis (ALS)-linked FUS variants sequester other paraspeckle proteins into aggregates formed in cultured cells and into neuronal inclusions in a transgenic mouse model of FUSopathy. Furthermore, we detected abundant p54nrb/NONO-positive inclusions in motor neurons of patients with familial forms of ALS caused by FUS mutations, but not in other ALS cases. Our results suggest that both loss and gain of FUS function can trigger disruption of paraspeckle assembly, which may impair protective responses in neurons and thereby contribute to the pathogenesis of FUSopathies.
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影响因子：
56.9
作者：
Kwiatkowski, T. J., Jr.;Bosco, D. A.;Brown, R. H., Jr.
通讯作者：
Brown, R. H., Jr.
影响因子：
3.5
作者：
Armstrong, Gary A. B.;Drapeau, Pierre
通讯作者：
Drapeau, Pierre
影响因子：
3.7
作者：
Meissner, M;Lopato, S;Barta, A
通讯作者：
Barta, A
影响因子：
7.2
作者：
Fox, Archa H.;Lamond, Angus I.
通讯作者：
Lamond, Angus I.
影响因子：
5.7
作者：
Da Cruz S;Cleveland DW
通讯作者：
Cleveland DW