- Fang, Mark Y;
- Markmiller, Sebastian;
- Vu, Anthony Q;
- Javaherian, Ashkan;
- Dowdle, William E;
- Jolivet, Philippe;
- Bushway, Paul J;
- Castello, Nicholas A;
- Baral, Ashmita;
- Chan, Michelle Y;
- Linsley, Jeremy W;
- Linsley, Drew;
- Mercola, Mark;
- Finkbeiner, Steven;
- Lecuyer, Eric;
- Lewcock, Joseph W;
- Yeo, Gene W
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.