Cytoplasmic TDP-43 De-mixing Independent of Stress Granules Drives Inhibition of Nuclear Import, Loss of Nuclear TDP-43, and Cell Death
Cytoplasmic TDP-43 De-mixing Independent of Stress Granules Drives Inhibition of Nuclear Import, Loss of Nuclear TDP-43, and Cell Death
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DOI：
10.1016/j.neuron.2019.02.038
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发表时间：
2019-04-17
期刊：
影响因子：
16.2
通讯作者：
Cleveland, Don W.
中科院分区：
文献类型：
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作者：
Gasset-Rosa, Fatima;Lu, Shan;Cleveland, Don W.
虽然TDP-43的细胞质聚集是肌萎缩侧索硬化症和额颞叶痴呆的病理标志，但尚未确定聚集体如何形成以及是什么驱动其核清除。在这里，我们表明，TDP-43在其内源性水平进行液-液相分离（LLPS）在多种细胞类型的细胞核内。TDP-43在细胞质中的浓度增加或瞬时暴露于超声处理的淀粉样原纤维显示引起胞质TDP-43的长寿命液滴，其组装和维持独立于常规应力颗粒。TDP-43的胞质液滴积累磷酸化TDP-43，并响应于短暂的亚砷酸盐介导的应激而迅速转化为凝胶/固体。胞质TDP-43液滴缓慢募集importin-oc和Nup 62并诱导RanGaol、Ran和Nup 107的错误定位，从而引起核质转运的抑制、核TDP-43的清除和细胞死亡。这些发现确定了一种神经元细胞死亡机制，该机制可由短暂应激诱导的TDP-43胞质解混引发。
While cytoplasmic aggregation of TDP-43 is a pathological hallmark of amyotrophic lateral sclerosis and frontotemporal dementia, how aggregates form and what drives its nuclear clearance have not been determined. Here we show that TDP-43 at its endogenous level undergoes liquid-liquid phase separation (LLPS) within nuclei in multiple cell types. Increased concentration of TDP-43 in the cytoplasm or transient exposure to sonicated amyloid-like fibrils is shown to provoke long-lived liquid droplets of cytosolic TDP-43 whose assembly and maintenance are independent of conventional stress granules. Cytosolic liquid droplets of TDP-43 accumulate phosphorylated TDP-43 and rapidly convert into gels/ solids in response to transient, arsenite-mediated stress. Cytoplasmic TDP-43 droplets slowly recruit importin-oc and Nup62 and induce mislocalization of RanGaol, Ran, and Nup107, thereby provoking inhibition of nucleocytoplasmic transport, clearance of nuclear TDP-43, and cell death. These findings identify a neuronal cell death mechanism that can be initiated by transient-stress-induced cytosolic de-mixing of TDP-43.