{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T04:58:26Z","timestamp":1791781106129,"version":"4.3.4"},"reference-count":99,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"848","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Signal."],"published-print":{"date-parts":[[2024,8,6]]},"abstract":"<jats:p>\n            Hexanucleotide repeat expansion in the\n            <jats:italic>C9ORF72<\/jats:italic>\n            gene is the most frequent inherited cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The expansion results in multiple dipeptide repeat proteins, among which arginine-rich poly-GR proteins are highly toxic to neurons and decrease the rate of protein synthesis. We investigated whether the effect on protein synthesis contributes to neuronal dysfunction and degeneration. We found that the expression of poly-GR proteins inhibited global translation by perturbing translation elongation. In iPSC-differentiated neurons, the translation of transcripts with relatively slow elongation rates was further slowed, and stalled, by poly-GR. Elongation stalling increased ribosome collisions and induced a ribotoxic stress response (RSR) mediated by ZAK\u03b1 that increased the phosphorylation of the kinase p38 and promoted cell death. Knockdown of ZAK\u03b1 or pharmacological inhibition of p38 ameliorated poly-GR\u2013induced toxicity and improved the survival of iPSC\u2013derived neurons from patients with\n            <jats:italic>C9ORF72<\/jats:italic>\n            -ALS\/FTD. Our findings suggest that targeting the RSR may be neuroprotective in patients with ALS\/FTD caused by repeat expansion in\n            <jats:italic>C9ORF72<\/jats:italic>\n            .\n          <\/jats:p>","DOI":"10.1126\/scisignal.adl1030","type":"journal-article","created":{"date-parts":[[2024,8,6]],"date-time":"2024-08-06T17:58:16Z","timestamp":1722967096000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":24,"title":["Poly-GR repeats associated with ALS\/FTD gene\n            <i>C9ORF72<\/i>\n            impair translation elongation and induce a ribotoxic stress response in neurons"],"prefix":"10.1126","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-6892-4857","authenticated-orcid":true,"given":"Daoyuan","family":"Dong","sequence":"first","affiliation":[{"name":"Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA."},{"name":"Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3952-2722","authenticated-orcid":true,"given":"Zhe","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA."},{"name":"Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2213-0650","authenticated-orcid":true,"given":"Yini","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA."},{"name":"Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malgorzata J.","family":"Latallo","sequence":"additional","affiliation":[{"name":"Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA."},{"name":"Center for Cell Dynamics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaopeng","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA."},{"name":"Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA."},{"name":"Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0678-1501","authenticated-orcid":true,"given":"Blake","family":"Nelson","sequence":"additional","affiliation":[{"name":"Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA."},{"name":"Center for Cell Dynamics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4506-3764","authenticated-orcid":true,"given":"Rong","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA."},{"name":"Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gopinath","family":"Krishnan","sequence":"additional","affiliation":[{"name":"RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fen-Biao","family":"Gao","sequence":"additional","affiliation":[{"name":"RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA."},{"name":"Department of Neurology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9442-3041","authenticated-orcid":true,"given":"Bin","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA."},{"name":"Center for Cell Dynamics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA."},{"name":"Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8449-7370","authenticated-orcid":true,"given":"Shuying","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA."},{"name":"Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA."},{"name":"Center for Cell Dynamics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA."},{"name":"Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA."},{"name":"Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41582-020-00434-z"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awac077"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2011.09.011"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2011.09.010"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2013.02.004"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1232927"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1315438110"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1256800"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2014.12.010"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2017.02.013"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.10.002"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1254917"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddv005"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1080\/19491034.2016.1172152"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abg3013"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2016.09.015"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-017-1793-8"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1186\/s40478-018-0564-7"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddw052"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.26508\/lsa.201800070"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-018-1946-4"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1074\/mcp.RA119.001888"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-018-0071-1"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-17129-0"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-30418-0"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkaa757"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00294-020-01111-w"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.abl6324"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.06.006"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrep.2017.08.002"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.1314"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.10.002"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-21637-y"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaf0899"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaf1084"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.04.034"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1038\/nbt1172"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2019.07.014"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1002\/cpcb.51"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1111\/acel.13549"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0127376"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2018.02.011"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1038\/emboj.2011.93"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2018.05.007"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2020.107610"},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-020-02256-0"},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2020.06.010"},{"key":"e_1_3_2_49_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-021-01006-0"},{"key":"e_1_3_2_50_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.60038"},{"key":"e_1_3_2_51_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2016.12.026"},{"key":"e_1_3_2_52_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkz1201"},{"key":"e_1_3_2_53_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2020.03.021"},{"key":"e_1_3_2_54_2","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2015.379"},{"key":"e_1_3_2_55_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4939-6955-5_9"},{"key":"e_1_3_2_56_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddaa106"},{"key":"e_1_3_2_57_2","doi-asserted-by":"publisher","DOI":"10.1111\/febs.13250"},{"key":"e_1_3_2_58_2","doi-asserted-by":"publisher","DOI":"10.1517\/13543780903321490"},{"key":"e_1_3_2_59_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2007.07.016"},{"key":"e_1_3_2_60_2","doi-asserted-by":"publisher","DOI":"10.1021\/ml2001455"},{"key":"e_1_3_2_61_2","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-150277"},{"key":"e_1_3_2_62_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-32944-3"},{"key":"e_1_3_2_63_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2013.10.015"},{"key":"e_1_3_2_64_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2022.102774"},{"key":"e_1_3_2_65_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awac479"},{"key":"e_1_3_2_66_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2021.103221"},{"key":"e_1_3_2_67_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M413059200"},{"key":"e_1_3_2_68_2","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2020.570586"},{"key":"e_1_3_2_69_2","first-page":"969","article-title":"Mitogen-activated protein kinase pathway in amyotrophic lateral sclerosis","volume":"9","author":"Sahana T. G.","year":"2021","unstructured":"T. G. Sahana, K. Zhang, Mitogen-activated protein kinase pathway in amyotrophic lateral sclerosis. Biomedicine 9, 969 (2021).","journal-title":"Biomedicine"},{"key":"e_1_3_2_70_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21165624"},{"key":"e_1_3_2_71_2","doi-asserted-by":"publisher","DOI":"10.1155\/2012\/649079"},{"key":"e_1_3_2_72_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21155485"},{"key":"e_1_3_2_73_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-018-0624-8"},{"key":"e_1_3_2_74_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-00091-1"},{"key":"e_1_3_2_75_2","doi-asserted-by":"publisher","DOI":"10.1093\/jnen\/63.2.113"},{"key":"e_1_3_2_76_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1044-7431(03)00022-8"},{"key":"e_1_3_2_77_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.02-0314fje"},{"key":"e_1_3_2_78_2","doi-asserted-by":"publisher","DOI":"10.1002\/ar.21047"},{"key":"e_1_3_2_79_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4578-12.2013"},{"key":"e_1_3_2_80_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2006.12.023"},{"key":"e_1_3_2_81_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.0c01773"},{"key":"e_1_3_2_82_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.9b00058"},{"key":"e_1_3_2_83_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13195-021-00843-2"},{"key":"e_1_3_2_84_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-022-09593-z"},{"key":"e_1_3_2_85_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-019-0397-0"},{"key":"e_1_3_2_86_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-024-01589-4"},{"key":"e_1_3_2_87_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abb3774"},{"key":"e_1_3_2_88_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.19760"},{"key":"e_1_3_2_89_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2021.01.029"},{"key":"e_1_3_2_90_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-41339-x"},{"key":"e_1_3_2_91_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms7171"},{"key":"e_1_3_2_92_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-30387-4"},{"key":"e_1_3_2_93_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btu170"},{"key":"e_1_3_2_94_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-12-323"},{"key":"e_1_3_2_95_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12859-017-1996-y"},{"key":"e_1_3_2_96_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-14-128"},{"key":"e_1_3_2_97_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-023-01374-9"},{"key":"e_1_3_2_98_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.3256"},{"key":"e_1_3_2_99_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.1551"},{"key":"e_1_3_2_100_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.1237"}],"container-title":["Science Signaling"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/scisignal.adl1030","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,8,6]],"date-time":"2024-08-06T17:58:22Z","timestamp":1722967102000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/scisignal.adl1030"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,8,6]]},"references-count":99,"journal-issue":{"issue":"848","published-print":{"date-parts":[[2024,8,6]]}},"alternative-id":["10.1126\/scisignal.adl1030"],"URL":"https:\/\/doi.org\/10.1126\/scisignal.adl1030","relation":{},"ISSN":["1945-0877","1937-9145"],"issn-type":[{"value":"1945-0877","type":"print"},{"value":"1937-9145","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,8,6]]},"assertion":[{"value":"2023-09-28","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-07-05","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-08-06","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"eadl1030"}}