RNA Binding Antagonizes Neurotoxic Phase Transitions of TDP-43
RNA Binding Antagonizes Neurotoxic Phase Transitions of TDP-43
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DOI：
10.1016/j.neuron.2019.01.048
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发表时间：
2019-04-17
期刊：
影响因子：
16.2
通讯作者：
Donnelly, Christopher J.
中科院分区：
文献类型：
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作者：
Mann, Jacob R.;Gleixner, Amanda M.;Donnelly, Christopher J.
TDP-43蛋白病是肌萎缩侧索硬化症和额颞叶痴呆的病理标志，在患者死后组织的退化区域内观察到细胞质TDP-43内含物。由于技术限制，TDP-43 聚集的机制仍然难以捉摸，这阻碍了对活细胞中特定 TDP-43 相互作用的分析。我们提出了一种在时空控制下可靠诱导 TDP-43 蛋白病的光遗传学方法。我们表明，病理相关内含物的形成是由 TDP-43 低复杂性结构域之间的异常相互作用驱动的，这些结构域被 RNA 结合拮抗。尽管应激颗粒被假设为传播 TDP-43 蛋白病的渠道，但我们证明了这些富含 RNA 的结构之外的病理内含物。此外，我们发现细胞质 TDP-43 的异常相变具有神经毒性，用由 TDP-43 靶序列组成的寡核苷酸处理可以防止包涵体并挽救神经毒性。总的来说，这些研究深入了解了 TDP-43 蛋白病的机制，并为治疗干预提供了潜在的途径。
TDP-43 proteinopathy is a pathological hallmark of amyotrophic lateral sclerosis and frontotemporal dementia where cytoplasmic TDP-43 inclusions are observed within degenerating regions of patient postmortem tissue. The mechanism by which TDP-43 aggregates has remained elusive due to technological limitations, which prevent the analysis of specific TDP-43 interactions in live cells. We present an optogenetic approach to reliably induce TDP-43 proteinopathy under spatiotemporal control. We show that the formation of pathologically relevant inclusions is driven by aberrant interactions between low-complexity domains of TDP-43 that are antagonized by RNA binding. Although stress granules are hypothesized to be a conduit for seeding TDP-43 proteinopathy, we demonstrate pathological inclusions outside these RNA-rich structures. Furthermore, we show that aberrant phase transitions of cytoplasmic TDP-43 are neurotoxic and that treatment with oligonucleotides composed of TDP-43 target sequences prevent inclusions and rescue neurotoxicity. Collectively, these studies provide insight into the mechanisms that underlie TDP-43 proteinopathy and present a potential avenue for therapeutic intervention.