Small-Molecule Modulation of TDP-43 Recruitment to Stress Granules Prevents Persistent TDP-43 Accumulation in ALS/FTD

Publication date: Available online 1 July 2019Source: NeuronAuthor(s): Mark Y. Fang, Sebastian Markmiller, Anthony Q. Vu, Ashkan Javaherian, William E. Dowdle, Philippe Jolivet, Paul J. Bushway, Nicholas A. Castello, Ashmita Baral, Michelle Y. Chan, Jeremy W. Linsley, Drew Linsley, Mark Mercola, Steven Finkbeiner, Eric Lecuyer, Joseph W. Lewcock, Gene W. YeoSummaryStress 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.Graphical Abstract

Source: Neuron - July 2, 2019 Category: Neuroscience Source Type: research