RNA Binding Antagonizes Neurotoxic Phase Transitions of TDP-43,Neuron

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RNA Binding Antagonizes Neurotoxic Phase Transitions of TDP-43
Neuron ( IF 14.7 ) Pub Date : 2019-02-27 , DOI: 10.1016/j.neuron.2019.01.048
Jacob R Mann ₁ , Amanda M Gleixner ₂ , Jocelyn C Mauna ₂ , Edward Gomes ₃ , Michael R DeChellis-Marks ₁ , Patrick G Needham ₄ , Katie E Copley ₂ , Bryan Hurtle ₂ , Bede Portz ₃ , Noah J Pyles ₂ , Lin Guo ₃ , Christopher B Calder ₂ , Zachary P Wills ₅ , Udai B Pandey ₆ , Julia K Kofler ₇ , Jeffrey L Brodsky ₈ , Amantha Thathiah ₅ , James Shorter ₃ , Christopher J Donnelly ₉

Affiliation

Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; LiveLikeLou Center for ALS Research, University of Pittsburgh Brain Institute, Pittsburgh, PA 15213, USA; Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; LiveLikeLou Center for ALS Research, University of Pittsburgh Brain Institute, Pittsburgh, PA 15213, USA.
Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
Department of Biological Sciences, Kenneth P. Dietrich School of Arts and Sciences, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA 15213, USA.
LiveLikeLou Center for ALS Research, University of Pittsburgh Brain Institute, Pittsburgh, PA 15213, USA; Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA 15213, USA; Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA 15213, USA.
LiveLikeLou Center for ALS Research, University of Pittsburgh Brain Institute, Pittsburgh, PA 15213, USA; Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Department of Biological Sciences, Kenneth P. Dietrich School of Arts and Sciences, University of Pittsburgh, Pittsburgh, PA 15213, USA; Center for Protein Conformational Diseases, Kenneth P. Dietrich School of Arts and Sciences, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; LiveLikeLou Center for ALS Research, University of Pittsburgh Brain Institute, Pittsburgh, PA 15213, USA; Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA 15213, USA; Center for Protein Conformational Diseases, Kenneth P. Dietrich School of Arts and Sciences, University of Pittsburgh, Pittsburgh, PA 15213, USA.

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.

中文翻译：

RNA 结合拮抗 TDP-43 的神经毒性相变

TDP-43 蛋白病是肌萎缩性侧索硬化和额颞叶痴呆的病理学标志，其中在患者尸检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地诱导 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 的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 结合所拮抗。尽管应激颗粒被假设为播种 TDP-43 蛋白病的管道，但我们证明了这些富含 RNA 的结构之外的病理内含物。此外，我们表明细胞质 TDP-43 的异常相变具有神经毒性，并且使用由 TDP-43 靶序列组成的寡核苷酸进行治疗可防止内含物并挽救神经毒性。总的来说，这些研究提供了对 TDP-43 蛋白病潜在机制的深入了解，并提供了治疗干预的潜在途径。

更新日期：2019-02-27

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