isogenic fus-egfp ipsc reporter lines enable quantification of fus stress granule pathology that is rescued by drugs inducing autophagy

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ID: 152666
2018
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Ranked #7 of 101 articles by views in nature reviews gastroenterology & hepatology

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Abstract
Summary: 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. : Sterneckert and colleagues generate isogenic FUS-eGFP reporter iPSCs that enable the identification of stress granule (SG) phenotypes specifically induced by the ALS mutation FUS P525L. Compound screening shows that modulation of the PI3K/AKT/mTOR pathway regulating autophagy ameliorates SG phenotypes. A second screen identifies similarly acting brain-penetrant US FDA-approved drugs that could be repurposed to treat ALS. Keywords: amyotrophic lateral sclerosis, induced pluripotent stem cells, FUS, stress granules, autophagy, gene editing, CRISPR/Cas9n
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marrone2018stemisogenic Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors ;Lara Marrone;Ina Poser;Ian Casci;Julia Japtok;Peter Reinhardt;Antje Janosch;Cordula Andree;Hyun O. Lee;Claudia Moebius;Ellen Koerner;Lydia Reinhardt;Maria Elena Cicardi;Karl Hackmann;Barbara Klink;Angelo Poletti;Simon Alberti;Marc Bickle;Andreas Hermann;Udai Bhan Pandey;Anthony A. Hyman;Jared L. Sterneckert
Journal nature reviews gastroenterology & hepatology
Year 2018
DOI
DOI not found
URL
http://www.sciencedirect.com/science/article/pii/S2213671117305660
Keywords
medicine (general)biology (general)

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