@article{e15ac126ccaa42afaf58e03dc606d01c,
title = "Overriding fus autoregulation in mice triggers gain-of-toxic dysfunctions in rna metabolism and autophagy-lysosome axis",
abstract = "Mutations in coding and non-coding regions of FUS cause amyotrophic lateral sclerosis (ALS). The latter mutations may exert toxicity by increasing FUS accumulation. We show here that broad expression within the nervous system of wild-type or either of two ALS-linked mutants of human FUS in mice produces progressive motor phenotypes accompanied by characteristic ALS-like pathology. FUS levels are autoregulated by a mechanism in which human FUS downregulates endogenous FUS at mRNA and protein levels. Increasing wild-type human FUS expression achieved by saturating this autoregulatory mechanism produces a rapidly progressive phenotype and dose-dependent lethality. Transcriptome analysis reveals mis-regulation of genes that are largely not observed upon FUS reduction. Likely mechanisms for FUS neurotoxicity include autophagy inhibition and defective RNA metabolism. Thus, our results reveal that overriding FUS autoregulation will trigger gain-of-function toxicity via altered autophagy-lysosome pathway and RNA metabolism function, highlighting a role for protein and RNA dyshomeostasis in FUS-mediated toxicity.",
author = "Ling, {Shuo Chien} and Dastidar, {Somasish Ghosh} and Seiya Tokunaga and Ho, {Wan Yun} and Kenneth Lim and Hristelina Ilieva and Parone, {Philippe A.} and Tyan, {Sheue Houy} and Tse, {Tsemay M.} and Chang, {Jer Cherng} and Oleksandr Platoshyn and Bui, {Ngoc B.} and Anh Bui and Anne Vetto and Shuying Sun and Melissa McAlonis-Downes and Han, {Joo Seok} and Debbie Swing and Katannya Kapeli and Yeo, {Gene W.} and Lino Tessarollo and Martin Marsala and Shaw, {Christopher E.} and Greg Tucker-Kellogg and {La Spada}, {Albert R.} and Clotilde Lagier-Tourenne and {Da Cruz}, Sandrine and Cleveland, {Don W.}",
note = "Funding Information: We are grateful for the help of Janet Folmer (The John Hopkins University, Baltimore, MD), Ying Jones and Timothy Meerloo (University of California at San Diego, La Jolla, CA) for section and technical support for the electron microscope, Kristen Watanabe, Christie Duong, Erik Balinghasay, Kevin Clutario, Kevin Drenner, Sandra Lee, and Jihane Boubaker for technical assistance. This work was supported by grants to DWC from the NIH and Wellcome trust, to ARL from the NIH (R01 AG033082 and R01 NS041648), and to S-C L from the Swee Liew-Wadsworth Endowment fund, National University of Singapore (NUS), National Medical Research Council (NMRC/OFIRG/0001/ 2016 and NMRC/OFIRG/0042/2017) and Ministry of Education (MOE2016-T2-1-024), Singapore. S-C Ling dedicates this work to Sheue-Houy Tyan. Funding Information: We are grateful for the help of Janet Folmer (The John Hopkins University, Baltimore, MD), Ying Jones and Timothy Meerloo (University of California at San Diego, La Jolla, CA) for section and technical support for the electron microscope, Kristen Watanabe, Christie Duong, Erik Balinghasay, Kevin Clutario, Kevin Drenner, Sandra Lee, and Jihane Boubaker for technical assistance. This work was supported by grants to DWC from the NIH and Wellcome trust, to ARL from the NIH (R01 AG033082 and R01 NS041648), and to S-C L from the Swee Liew-Wadsworth Endowment fund, National University of Singapore (NUS), National Medical Research Council (NMRC/OFIRG/0001/ 2016 and NMRC/OFIRG/0042/2017) and Ministry of Education (MOE 2016-T2-1-024), Singapore. S-C Ling dedicates this work to Sheue-Houy Tyan. Publisher Copyright: {\textcopyright} 2019, eLife Sciences Publications Ltd. All rights reserved.",
year = "2019",
doi = "10.7554/eLife.40811",
language = "English (US)",
volume = "8",
journal = "eLife",
issn = "2050-084X",
publisher = "eLife Sciences Publications",
}