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

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

Author information

1
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Stem Cell Program, University of California, San Diego, La Jolla, CA 92093, USA; Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
2
Gladstone Institutes, San Francisco, CA 94158, USA.
3
Denali Therapeutics Inc., South San Francisco, CA 94080, USA.
4
Institut de Recherches Cliniques de Montréal, Montréal, Québec H2W 1R7, Canada.
5
Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA; Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093.
6
Brown University, Department of Cognitive, Linguistic and Psychological Sciences, Providence, RI 02912, USA.
7
Taube/Koret Center for Neurodegenerative Disease Research and DaedalusBio, Gladstone Institutes, San Francisco, CA 94158, USA; Departments of Neurology and Physiology, University of California, San Francisco, San Francisco, CA 94158, USA.
8
Institut de Recherches Cliniques de Montréal, Montréal, Québec H2W 1R7, Canada; Département de Biochimie et Médecine Moléculaire, Université de Montréal, Montréal, Québec H3C 3J7, Canada; Division of Experimental Medicine, McGill University, Montréal, Québec H3A 1A3, Canada.
9
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Stem Cell Program, University of California, San Diego, La Jolla, CA 92093, USA; Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: geneyeo@ucsd.edu.

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.

KEYWORDS:

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

PMID:
31272829
PMCID:
PMC6728177
[Available on 2020-09-04]
DOI:
10.1016/j.neuron.2019.05.048

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