Small-Molecule Modulation of TDP-43 Recruitment to Stress Granules Prevents Persistent TDP-43 Accumulation in ALS/FTD
Small-Molecule Modulation of TDP-43 Recruitment to Stress Granules Prevents Persistent TDP-43 Accumulation in ALS/FTD
复制标题
DOI：
10.1016/j.neuron.2019.05.048
复制
发表时间：
2019-09-04
期刊：
影响因子：
16.2
通讯作者：
Yeo, Gene W.
中科院分区：
文献类型：
--
作者：
Fang, Mark Y.;Markmiller, Sebastian;Yeo, Gene W.
应激颗粒（SG）在细胞应激期间形成，并与神经退行性疾病如肌萎缩侧索硬化和额颞叶痴呆（ALS/FTD）有关。为了深入了解SG在病理生理学中的作用，我们进行了高含量筛选以鉴定改变增殖细胞和人iPSC衍生的运动神经元（iPS-MN）中SG性质的小分子。一类主要的活性分子含有扩展的平面芳香族部分，这表明有可能嵌入核酸中。因此，我们表明，几种命中化合物可以防止ALS相关的RNA结合蛋白（RBP）TDP-43，FUS和HNRNPA 2B 1进入SG的RNA依赖性募集。我们进一步证明，瞬时SG形成有助于TDP-43持续积累到细胞质斑点中，并且我们的命中化合物可以减少ALS患者的iPS-MN中的这种积累。我们提出，平面部分的化合物代表了一个有前途的起点，开发小分子治疗ALS/FTD的治疗。
Stress granules (SGs) form during cellular stress and are implicated in neurodegenerative diseases such as amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). To yield insights into the role of SGs in pathophysiology, we performed a high content screen to identify small molecules that alter SG properties in proliferative cells and human iPSC-derived motor neurons (iPS-MNs). One major class of active molecules contained extended planar aromatic moieties, suggesting a potential to intercalate in nucleic acids. Accordingly, we show that several hit compounds can prevent the RNA-dependent recruitment of the ALS-associated RNA-binding proteins (RBPs) TDP-43, FUS, and HNRNPA2B1 into SGs. We further demonstrate that transient SG formation contributes to persistent accumulation of TDP-43 into cytoplasmic puncta and that our hit compounds can reduce this accumulation in iPS-MNs from ALS patients. We propose that compounds with planar moieties represent a promising starting point to develop small-molecule therapeutics for treating ALS/FTD.