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Stem Cell Reports. 2018 Feb 13;10(2):375-389. doi: 10.1016/j.stemcr.2017.12.018. Epub 2018 Jan 18.

Isogenic FUS-eGFP iPSC Reporter Lines Enable Quantification of FUS Stress Granule Pathology that Is Rescued by Drugs Inducing Autophagy.

Author information

1
DFG-Center for Regenerative Therapies, Technische Universität Dresden, Fetscherstrasse 105, 01307 Dresden, Germany.
2
Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany.
3
Department of Pediatrics, Division of Child Neurology, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA.
4
Department of Neurology, Technische Universität Dresden, 01307 Dresden, Germany.
5
DFG-Center for Regenerative Therapies, Technische Universität Dresden, Fetscherstrasse 105, 01307 Dresden, Germany; Currently at AbbVie Deutschland GmbH & Co KG, Neuroscience Discovery - Biology Department, Knollstrasse, 67061 Ludwigshafen, Germany.
6
Department of Pharmacological and Biomolecular Sciences, Centre of Excellence on Neurodegenerative Diseases University of Milan, Milan 20133, Italy.
7
Currently at AbbVie Deutschland GmbH & Co KG, Neuroscience Discovery - Biology Department, Knollstrasse, 67061 Ludwigshafen, Germany.
8
Institut für Klinische Genetik, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
9
DFG-Center for Regenerative Therapies, Technische Universität Dresden, Fetscherstrasse 105, 01307 Dresden, Germany; Department of Neurology, Technische Universität Dresden, 01307 Dresden, Germany; German Center for Neurodegenerative Diseases (DZNE), 01307 Dresden, Germany.
10
Department of Pediatrics, Division of Child Neurology, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA; Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
11
DFG-Center for Regenerative Therapies, Technische Universität Dresden, Fetscherstrasse 105, 01307 Dresden, Germany. Electronic address: jared.sterneckert@tu-dresden.de.

Abstract

Perturbations in stress granule (SG) dynamics may be at the core of amyotrophic lateral sclerosis (ALS). Since SGs are membraneless compartments, modeling their dynamics in human motor neurons has been challenging, thus hindering the identification of effective therapeutics. Here, we report the generation of isogenic induced pluripotent stem cells carrying wild-type and P525L FUS-eGFP. We demonstrate that FUS-eGFP is recruited into SGs and that P525L profoundly alters their dynamics. With a screening campaign, we demonstrate that PI3K/AKT/mTOR pathway inhibition increases autophagy and ameliorates SG phenotypes linked to P525L FUS by reducing FUS-eGFP recruitment into SGs. Using a Drosophila model of FUS-ALS, we corroborate that induction of autophagy significantly increases survival. Finally, by screening clinically approved drugs for their ability to ameliorate FUS SG phenotypes, we identify a number of brain-penetrant anti-depressants and anti-psychotics that also induce autophagy. These drugs could be repurposed as potential ALS treatments.

KEYWORDS:

CRISPR/Cas9n; FUS; amyotrophic lateral sclerosis; autophagy; gene editing; induced pluripotent stem cells; stress granules

PMID:
29358088
PMCID:
PMC5857889
DOI:
10.1016/j.stemcr.2017.12.018
[Indexed for MEDLINE]
Free PMC Article

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