Small molecule modulation of TDP-43 recruitment to stress granules prevents persistent TDP-43 accumulation in ALS/FTD
| Autor: | Sebastian Markmiller, Jeremy W. Linsley, William E. Dowdle, Drew Linsley, Anthony Q. Vu, Mark Mercola, Gene W. Yeo, Michelle Y. Chan, Ashmita Baral, Joseph W. Lewcock, Philippe Jolivet, Steven Finkbeiner, Nicholas A. Castello, Ashkan Javaherian, Paul J. Bushway, Eric Lécuyer, Mark Y. Fang |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Induced Pluripotent Stem Cells Cytoplasmic Granules Protein Aggregation Pathological Article Cell Line Small Molecule Libraries 03 medical and health sciences 0302 clinical medicine Stress granule Neural Stem Cells Stress Physiological Heterogeneous-Nuclear Ribonucleoprotein Group A-B medicine Humans Amyotrophic lateral sclerosis Poly-ADP-Ribose Binding Proteins Motor Neurons Chemistry General Neuroscience Amyotrophic Lateral Sclerosis DNA Helicases medicine.disease Small molecule Cell biology High-Throughput Screening Assays DNA-Binding Proteins Intrinsically Disordered Proteins 030104 developmental biology HEK293 Cells RNA Recognition Motif Proteins Cytoplasm High-content screening Frontotemporal Dementia Nucleic acid RNA-Binding Protein FUS 030217 neurology & neurosurgery RNA Helicases Frontotemporal dementia |
| Zdroj: | Neuron |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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