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

First Authors Lara Marrone
Authors Lara Marrone, Ina Poser, Ian Casci, Julia Japtok, Peter Reinhardt, Antje Janosch, Cordula Andree, Hyun-Ok Kate Lee, Claudia Moebius, Ellen Koerner, Lydia Reinhardt, Maria Elena Cicardi, Karl Hackmann, Barbara Klink, Angelo Poletti, Simon Alberti, Marc Bickle, Andreas Hermann, Udai Pandey, Anthony Hyman, Jared Sterneckert
Corresponding Authors
Last Authors Jared Sterneckert
Journal Name Stem cell reports (Stem Cell Rep)
Volume 10
Issue 2
Page Range 375-389
Open Access true
Print Publication Date 2018-02-13
Online Publication Date
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.
Cover Image
Affiliated With Alberti, Hyman, Postdocs, Technology Development Studio TDS
Selected By
Acknowledged Services
Publication Status Published
Edoc Link
Sfx Link
DOI 10.1016/j.stemcr.2017.12.018
PubMed ID 29358088
WebOfScience Link WOS:000424907600007
Alternative Full Text URL
Display Publisher Download Only false
Visible On MPI-CBG Website true
PDF Downloadable true
Created By thuem
Added Date 2018-02-01
Last Edited By thuem
Last Edited Date 2018-03-01 11:50:34.969
Library ID 7052
Document ID
Entry Complete true
eDoc Compliant true
Include in Edoc Report true
In Pure
Ready for eDoc Export
Author Affiliations Complete false
Project Name
Project URL
Grant ID
Funding Programme
Funding Organisation