Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA 92093, USA.
Department of Anesthesiology, University of California at San Diego, La Jolla, CA 92093, USA.
Neuron. 2018 Nov 21;100(4):816-830.e7. doi: 10.1016/j.neuron.2018.09.044. Epub 2018 Oct 18.
Through the generation of humanized FUS mice expressing full-length human FUS, we identify that when expressed at near endogenous murine FUS levels, both wild-type and ALS-causing and frontotemporal dementia (FTD)-causing mutations complement the essential function(s) of murine FUS. Replacement of murine FUS with mutant, but not wild-type, human FUS causes stress-mediated induction of chaperones, decreased expression of ion channels and transporters essential for synaptic function, and reduced synaptic activity without loss of nuclear FUS or its cytoplasmic aggregation. Most strikingly, accumulation of mutant human FUS is shown to activate an integrated stress response and to inhibit local, intra-axonal protein synthesis in hippocampal neurons and sciatic nerves. Collectively, our evidence demonstrates that human ALS/FTD-linked mutations in FUS induce a gain of toxicity that includes stress-mediated suppression in intra-axonal translation, synaptic dysfunction, and progressive age-dependent motor and cognitive disease without cytoplasmic aggregation, altered nuclear localization, or aberrant splicing of FUS-bound pre-mRNAs. VIDEO ABSTRACT.
通过生成表达全长人 FUS 的人源化 FUS 小鼠，我们发现，当以接近内源性鼠 FUS 水平表达时，野生型和导致肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）的突变均能补充鼠 FUS 的基本功能。用突变型（而非野生型）人 FUS 替代鼠 FUS 会导致应激介导的伴侣蛋白诱导、离子通道和转运体表达减少，这些蛋白对于突触功能至关重要，从而导致突触活性降低，而核 FUS 或其胞质聚集并未丢失。最引人注目的是，突变型人 FUS 的积累被证明会激活整合应激反应，并抑制海马神经元和坐骨神经中的局部、轴内蛋白质合成。总的来说，我们的证据表明，FUS 中的人类 ALS/FTD 相关突变会引起毒性获得，包括应激介导的轴内翻译抑制、突触功能障碍以及进行性年龄依赖性运动和认知疾病，而不会导致细胞质聚集、核定位改变或 FUS 结合的 pre-mRNA 异常剪接。视频摘要。
