期刊
STEM CELL REPORTS
卷 10, 期 2, 页码 375-389出版社
CELL PRESS
DOI: 10.1016/j.stemcr.2017.12.018
关键词
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资金
- Deutsche Forschungsgemeinschaft (DFG)
- CRTD/TUD
- DFG Research Center [DFG FZ 111]
- Cluster of Excellence [DFG EXC 168]
- CRTD
- Hans and Ilse Breuer Stiftung
- CRTD Light Microscopy
- FACS facilities
- European Union's Horizon research and innovation program [643417]
- Bundesministerium fur Bildung und Forschung [01ED1601B]
- JPND: Germany, Bundesministerium fur Bildung und Forschung
- Israel, Ministry of Health
- Italy, Ministero dell'Istruzione dell'Universita e della Ricerca
- Sweden, Swedish Research Council
- Switzerland, Swiss National Science Foundation
- Robert Packard Center for ALS at Johns Hopkins
- USA National Institutes of Health [R21NS094921, R01NS081303, R21NS100055, R21NS098379]
- Muscular Dystrophy Association
- Deutsche Gesellschaft fur Muskelerkrankungen [He2/2]
- NOMIS Foundation
- Helmholtz Virtual Institute RNA dysmetabolism in ALS and FTD [VH-VI-510]
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.
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