Muscleblind acts as a modifier of FUS toxicity by modulating stress granule dynamics and SMN localization
Muscleblind acts as a modifier of FUS toxicity by modulating stress granule dynamics and SMN localization
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DOI：
10.1038/s41467-019-13383-z
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发表时间：
2019-12-06
影响因子：
16.6
通讯作者：
Pandey, Udai Bhan
中科院分区：
文献类型：
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作者：
Casci, Ian;Krishnamurthy, Karthik;Pandey, Udai Bhan
融合肉瘤（FUS）突变可导致肌萎缩侧索硬化症（ALS），其发病年龄、进展和严重程度各不相同。这表明未知的遗传因素参与了疾病的发病机制。在这里，我们展示了肌盲作为us介导的神经变性在体内的一种新的调节剂的鉴定。在哺乳动物神经元和人类ipsc来源的神经元中，Muscleblind调节突变FUS的细胞质错定位和随后在应激颗粒中的积累、树突形态和毒性。有趣的是，内源性肌肉盲的遗传调节足以恢复表达FUS致病性突变的神经元中存活的运动神经元（SMN）蛋白定位，这提示了抑制FUS毒性的潜在模式。SMN上调可抑制果蝇和初级皮质神经元的FUS毒性，表明FUS与SMN之间存在联系。我们的数据提供了体内证据，表明肌肉盲是fus介导的神经退行性变的主要调节剂，通过调节fus介导的ALS发病机制。
Mutations in fused in sarcoma (FUS) lead to amyotrophic lateral sclerosis (ALS) with varying ages of onset, progression and severity. This suggests that unknown genetic factors contribute to disease pathogenesis. Here we show the identification of muscleblind as a novel modifier of FUS-mediated neurodegeneration in vivo. Muscleblind regulates cytoplasmic mislocalization of mutant FUS and subsequent accumulation in stress granules, dendritic morphology and toxicity in mammalian neuronal and human iPSC-derived neurons. Interestingly, genetic modulation of endogenous muscleblind was sufficient to restore survival motor neuron (SMN) protein localization in neurons expressing pathogenic mutations in FUS, suggesting a potential mode of suppression of FUS toxicity. Upregulation of SMN suppressed FUS toxicity in Drosophila and primary cortical neurons, indicating a link between FUS and SMN. Our data provide in vivo evidence that muscleblind is a dominant modifier of FUS-mediated neurodegeneration by regulating FUS-mediated ALS pathogenesis.