1. Small-Molecule Modulation of TDP-43 Recruitment to Stress Granules Prevents Persistent TDP-43 Accumulation in ALS/FTD.
- Author
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Fang MY, Markmiller S, Vu AQ, Javaherian A, Dowdle WE, Jolivet P, Bushway PJ, Castello NA, Baral A, Chan MY, Linsley JW, Linsley D, Mercola M, Finkbeiner S, Lecuyer E, Lewcock JW, and Yeo GW
- Subjects
- Cell Line, Cytoplasmic Granules metabolism, DNA Helicases genetics, DNA-Binding Proteins metabolism, HEK293 Cells, Heterogeneous-Nuclear Ribonucleoprotein Group A-B metabolism, High-Throughput Screening Assays, Humans, Induced Pluripotent Stem Cells, Intrinsically Disordered Proteins, Motor Neurons metabolism, Neural Stem Cells drug effects, Neural Stem Cells metabolism, Poly-ADP-Ribose Binding Proteins genetics, RNA Helicases genetics, RNA Recognition Motif Proteins genetics, RNA-Binding Protein FUS metabolism, Amyotrophic Lateral Sclerosis metabolism, Cytoplasmic Granules drug effects, DNA-Binding Proteins drug effects, Frontotemporal Dementia metabolism, Motor Neurons drug effects, Protein Aggregation, Pathological metabolism, Small Molecule Libraries pharmacology, Stress, Physiological drug effects
- Abstract
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., (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Published
- 2019
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