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

Neuron. 2019 Sep 4;103(5):802-819.e11. doi: 10.1016/j.neuron.2019.05.048. Epub 2019 Jul 1.


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.

Keywords: ALS-FTD; TDP-43; high-content screening; motor neurons; planar molecule; stress granule.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis / metabolism*
  • Cell Line
  • Cytoplasmic Granules / drug effects*
  • Cytoplasmic Granules / metabolism
  • DNA Helicases / genetics
  • DNA-Binding Proteins / drug effects*
  • DNA-Binding Proteins / metabolism
  • Frontotemporal Dementia / metabolism*
  • HEK293 Cells
  • Heterogeneous-Nuclear Ribonucleoprotein Group A-B / metabolism
  • High-Throughput Screening Assays
  • Humans
  • Induced Pluripotent Stem Cells
  • Intrinsically Disordered Proteins
  • Motor Neurons / drug effects*
  • Motor Neurons / metabolism
  • Neural Stem Cells / drug effects
  • Neural Stem Cells / metabolism
  • Poly-ADP-Ribose Binding Proteins / genetics
  • Protein Aggregation, Pathological / metabolism*
  • RNA Helicases / genetics
  • RNA Recognition Motif Proteins / genetics
  • RNA-Binding Protein FUS / metabolism
  • Small Molecule Libraries / pharmacology*
  • Stress, Physiological / drug effects*


  • DNA-Binding Proteins
  • FUS protein, human
  • Heterogeneous-Nuclear Ribonucleoprotein Group A-B
  • Intrinsically Disordered Proteins
  • Poly-ADP-Ribose Binding Proteins
  • RNA Recognition Motif Proteins
  • RNA-Binding Protein FUS
  • Small Molecule Libraries
  • TARDBP protein, human
  • hnRNP A2
  • DNA Helicases
  • G3BP1 protein, human
  • RNA Helicases

Supplementary concepts

  • Frontotemporal Dementia With Motor Neuron Disease