Fused in sarcoma (FUS) protein lacking nuclear localization signal (NLS) and major RNA binding motifs triggers proteinopathy and severe motor phenotype in transgenic mice.
Fused in sarcoma (FUS) protein lacking nuclear localization signal (NLS) and major RNA binding motifs triggers proteinopathy and severe motor phenotype in transgenic mice.
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DOI：
10.1074/jbc.m113.492017
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发表时间：
2013-08-30
期刊：
影响因子：
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通讯作者：
Ninkina NN
中科院分区：
文献类型：
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作者：
Shelkovnikova TA;Peters OM;Deykin AV;Connor-Robson N;Robinson H;Ustyugov AA;Bachurin SO;Ermolkevich TG;Goldman IL;Sadchikova ER;Kovrazhkina EA;Skvortsova VI;Ling SC;Da Cruz S;Parone PA;Buchman VL;Ninkina NN
背景：FUS 内含物是某些神经退行性疾病的标志。结果：转基因小鼠中高度聚集倾向的 FUS 变体的表达会导致蛋白质病和严重的运动表型。结论：FUS 的聚集足以重现肌萎缩侧索硬化症典型的运动病理学。意义：了解蛋白质聚集在人类神经退行性疾病发展中的作用对于设计有效的治疗方法至关重要。两种结构和功能相关的蛋白质，即 43 kDa 的 FUS 和 TAR DNA 结合蛋白 (TDP-43) 的功能障碍，与细胞 RNA 代谢的关键步骤有关，可导致肌萎缩侧索硬化症 (ALS) 和某些其他神经退行性疾病。这些蛋白质本质上易于聚集，并在受影响的神经组织中形成非淀粉样蛋白内含物，但这些蛋白质聚集体在疾病发作和进展中的作用仍不确定。为了解决这个问题，我们设计了 FUS 的一个变体，FUS 1-359，它主要存在于细胞质中，高度聚集，并且缺乏负责 RNA 识别和结合的区域。 FUS 1-359 在转基因小鼠神经元中的表达水平低于内源性 FUS，可引发与运动神经元及其轴突严重损伤、神经炎症反应以及最终选择性运动神经元群丧失相关的 FUS 病。这些病理变化导致2.5-4.5个月大时突然出现严重的运动表型，并在发病后几天内导致受影响的动物死亡。转基因 FUS 1-359 小鼠的病理模式概括了人类 ALS 的几个关键特征，疾病进展的动态随着小鼠寿命的缩短而压缩。我们的数据表明，神经元 FUS 聚集足以在转基因小鼠中引起 ALS 样表型。
Background: FUS inclusions are hallmarks of certain neurodegenerative diseases. Results: Expression of a highly aggregate prone FUS variant in transgenic mice causes proteinopathy and severe motor phenotype. Conclusion: Aggregation of FUS is sufficient to recapitulate motor pathology typical for amyotrophic lateral sclerosis. Significance: Understanding the role of protein aggregation in the development of human neurodegenerative diseases is crucial for designing efficient therapeutic approaches. Dysfunction of two structurally and functionally related proteins, FUS and TAR DNA-binding protein of 43 kDa (TDP-43), implicated in crucial steps of cellular RNA metabolism can cause amyotrophic lateral sclerosis (ALS) and certain other neurodegenerative diseases. The proteins are intrinsically aggregate-prone and form non-amyloid inclusions in the affected nervous tissues, but the role of these proteinaceous aggregates in disease onset and progression is still uncertain. To address this question, we designed a variant of FUS, FUS 1–359, which is predominantly cytoplasmic, highly aggregate-prone, and lacks a region responsible for RNA recognition and binding. Expression of FUS 1–359 in neurons of transgenic mice, at a level lower than that of endogenous FUS, triggers FUSopathy associated with severe damage of motor neurons and their axons, neuroinflammatory reaction, and eventual loss of selective motor neuron populations. These pathological changes cause abrupt development of a severe motor phenotype at the age of 2.5–4.5 months and death of affected animals within several days of onset. The pattern of pathology in transgenic FUS 1–359 mice recapitulates several key features of human ALS with the dynamics of the disease progression compressed in line with shorter mouse lifespan. Our data indicate that neuronal FUS aggregation is sufficient to cause ALS-like phenotype in transgenic mice.