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Citation
Marrone, L., Poser, I., Casci, I., Japtok, J., Reinhardt, P., Janosch, A., Andree, C., Lee, H.O., Moebius, C., Koerner, E., Reinhardt, L., Cicardi, M.E., Hackmann, K., Klink, B., Poletti, A., Alberti, S., Bickle, M., Hermann, A., Pandey, U.B., Hyman, A.A., Sterneckert, J.L. (2018). Isogenic FUS-eGFP iPSC Reporter Lines Enable Quantification of FUS Stress Granule Pathology that Is Rescued by Drugs Inducing Autophagy.  Stem Cell Reports 10(2): 375--389.
FlyBase ID
FBrf0238148
Publication Type
Research paper
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.

PubMed ID
PubMed Central ID
PMC5857889 (PMC) (EuropePMC)
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Secondary IDs
    Language of Publication
    English
    Additional Languages of Abstract
    Parent Publication
    Publication Type
    Journal
    Abbreviation
    Stem Cell Reports
    Title
    Stem cell reports
    ISBN/ISSN
    2213-6711
    Data From Reference
    Genes (2)
    Human Disease Models (1)