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

Author

Marrone L, Poser I, Casci I, Japtok J, Reinhardt P, Janosch A, Andree C, Lee HO, Moebius C, Koerner E, Reinhardt L, Cicardi ME, Hackmann K, Klink B, Poletti A, Alberti S, Bickle M, Hermann A, Pandey UB, Hyman AA, and Sterneckert JL

Subjects
Amyotrophic Lateral Sclerosis metabolism, Amyotrophic Lateral Sclerosis pathology, Animals, Antidepressive Agents pharmacology, Antipyretics pharmacology, Autophagy genetics, CRISPR-Cas Systems, Drosophila, Drug Evaluation, Preclinical, Green Fluorescent Proteins genetics, Humans, Motor Neurons metabolism, Motor Neurons pathology, Mutation, Phosphatidylinositol 3-Kinases genetics, Proto-Oncogene Proteins c-akt genetics, Signal Transduction drug effects, TOR Serine-Threonine Kinases genetics, Amyotrophic Lateral Sclerosis genetics, Drosophila Proteins genetics, Heterogeneous-Nuclear Ribonucleoprotein Group F-H genetics, Induced Pluripotent Stem Cells metabolism, RNA-Binding Protein FUS genetics
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., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Published
2018
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2. A conserved RhoGAP limits M phase contractility and coordinates with microtubule asters to confine RhoA during cytokinesis.

Author

Zanin E, Desai A, Poser I, Toyoda Y, Andree C, Moebius C, Bickle M, Conradt B, Piekny A, and Oegema K

Subjects
Animals, Caenorhabditis elegans genetics, Caenorhabditis elegans growth & development, Cell Division genetics, Embryo, Nonmammalian cytology, Embryo, Nonmammalian metabolism, Gene Expression Regulation, Developmental, Microtubules genetics, Muscle Contraction genetics, rhoA GTP-Binding Protein metabolism, Cytokinesis genetics, GTPase-Activating Proteins genetics, Mitosis genetics, rhoA GTP-Binding Protein genetics
Abstract

During animal cell cytokinesis, the spindle directs contractile ring assembly by activating RhoA in a narrow equatorial zone. Rapid GTPase activating protein (GAP)-mediated inactivation (RhoA flux) is proposed to limit RhoA zone dimensions. Testing the significance of RhoA flux has been hampered by the fact that the GAP targeting RhoA is not known. Here, we identify M phase GAP (MP-GAP) as the primary GAP targeting RhoA during mitosis and cytokinesis. MP-GAP inhibition caused excessive RhoA activation in M phase, leading to the uncontrolled formation of large cortical protrusions and late cytokinesis failure. RhoA zone width was broadened by attenuation of the centrosomal asters but was not affected by MP-GAP inhibition alone. Simultaneous aster attenuation and MP-GAP inhibition led to RhoA accumulation around the entire cell periphery. These results identify the major GAP restraining RhoA during cell division and delineate the relative contributions of RhoA flux and centrosomal asters in controlling RhoA zone dimensions., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Published
2013
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