Optogenetic TDP-43 nucleation induces persistent insoluble species and progressive motor dysfunction in vivo.
Optogenetic TDP-43 nucleation induces persistent insoluble species and progressive motor dysfunction in vivo.
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DOI：
10.1016/j.nbd.2020.105078
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发表时间：
2020-12
影响因子：
6.1
通讯作者：
Donnelly, Christopher J.
中科院分区：
文献类型：
--
作者：
Otte, Charlton G.;Fortuna, Tyler R.;Mann, Jacob R.;Gleixner, Amanda M.;Ramesh, Nandini;Pyles, Noah J.;Pandey, Udai B.;Donnelly, Christopher J.
TDP-43 是一种主要的核 DNA/RNA 结合蛋白，在多种神经退行性疾病患者死后组织中，经常错误定位到不溶性细胞质包涵体中，最引人注目的是肌萎缩侧索硬化症 (ALS)，这是一种致命的进行性神经肌肉疾病。 TDP-43 蛋白病的根本原因尚不清楚，但最近的研究表明这些蛋白组装体的形成是由 RNA 缺陷 TDP-43 的异常相变驱动的。技术限制阻碍了我们理解 TDP-43 蛋白病与疾病发病机制之间的关系。目前的 TDP-43 蛋白病动物模型通常依赖于野生型 TDP-43 过度表达至非生理水平，这可能通过核功能获得机制或仅在一小部分 ALS 患者中发现的致病突变的表达来引发神经毒性。正如我们之前在体外所证明的那样，允许光响应控制亚细胞蛋白质拥挤的新技术提供了一种有前途的驱动细胞内蛋白质聚集的方法。在这里，我们提出了果蝇中 TDP-43 聚集的光遗传学诱导模型，该模型概括了患者病理学中观察到的关键生化特征，最显着的是光诱导的持久不溶性物质和进行性运动功能障碍。这些数据描述了一种光动力体内模型，该模型可以作为未来的平台来识别与 TDP-43 神经病理学相关疾病的新型遗传和药理学修饰剂。
TDP-43 is a predominantly nuclear DNA/RNA binding protein that is often mislocalized into insoluble cytoplasmic inclusions in post-mortem patient tissue in a variety of neurodegenerative disorders, most notably, Amyotrophic Lateral Sclerosis (ALS), a fatal and progressive neuromuscular disorder. The underlying causes of TDP-43 proteinopathies remain unclear, but recent studies indicate the formation of these protein assemblies is driven by aberrant phase transitions of RNA deficient TDP-43. Technical limitations have prevented our ability to understand how TDP-43 proteinopathy relates to disease pathogenesis. Current animal models of TDP-43 proteinopathy often rely on overexpression of wild-type TDP-43 to non-physiological levels that may initiate neurotoxicity through nuclear gain of function mechanisms, or by the expression of disease-causing mutations found in only a fraction of ALS patients. New technologies allowing for light-responsive control of subcellular protein crowding provide a promising approach to drive intracellular protein aggregation, as we have previously demonstrated in vitro. Here we present a model for the optogenetic induction of TDP-43 aggregation in Drosophila that recapitulates key biochemical features seen in patient pathology, most notably light-inducible persistent insoluble species and progressive motor dysfunction. These data describe a photokinetic in vivo model that could be as a future platform to identify novel genetic and pharmacological modifiers of diseases associated with TDP-43 neuropathology.
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影响因子：
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