FUS pathology in ALS is linked to alterations in multiple ALS-associated proteins and rescued by drugs stimulating autophagy
FUS pathology in ALS is linked to alterations in multiple ALS-associated proteins and rescued by drugs stimulating autophagy
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DOI：
10.1007/s00401-019-01998-x
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发表时间：
2019-07-01
影响因子：
12.7
通讯作者：
Sterneckert, Jared
中科院分区：
文献类型：
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作者：
Marrone, Lara;Drexler, Hannes C. A.;Sterneckert, Jared
肌萎缩侧索硬化症（ALS）是一种以运动神经元变性为特征的致死性疾病，与核RNA结合蛋白（RBP）（包括FUS）的聚集有关。如何在健康的运动神经元中防止FUS聚集和神经变性仍然是一个悬而未决的问题。在这里，我们使用ALS患者尸检组织和诱导多能干细胞衍生的神经元的组合来研究FUS突变对RBP稳态的影响。我们发现，FUS的聚集倾向通常是由相互作用的RBPs缓冲，但这种缓冲是失去了FUS由于ALS突变的细胞质定位错误。细胞质中存在聚集倾向的FUS导致RBP稳态失衡，从而加剧神经退行性变。然而，使用小分子增强自噬减少细胞质FUS，恢复RBP稳态并挽救体内运动功能。我们的结论是RBP稳态的破坏在FUS-ALS中起着关键作用，可以通过刺激自噬来治疗。
Amyotrophic lateral sclerosis (ALS) is a lethal disease characterized by motor neuron degeneration and associated with aggregation of nuclear RNA-binding proteins (RBPs), including FUS. How FUS aggregation and neurodegeneration are prevented in healthy motor neurons remain critically unanswered questions. Here, we use a combination of ALS patient autopsy tissue and induced pluripotent stem cell-derived neurons to study the effects of FUS mutations on RBP homeostasis. We show that FUS' tendency to aggregate is normally buffered by interacting RBPs, but this buffering is lost when FUS mislocalizes to the cytoplasm due to ALS mutations. The presence of aggregation-prone FUS in the cytoplasm causes imbalances in RBP homeostasis that exacerbate neurodegeneration. However, enhancing autophagy using small molecules reduces cytoplasmic FUS, restores RBP homeostasis and rescues motor function in vivo. We conclude that disruption of RBP homeostasis plays a critical role in FUS-ALS and can be treated by stimulating autophagy.