{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,18]],"date-time":"2026-07-18T14:23:14Z","timestamp":1784384594174,"version":"3.55.0"},"reference-count":83,"publisher":"The Royal Society","issue":"4","license":[{"start":{"date-parts":[[2023,4,1]],"date-time":"2023-04-01T00:00:00Z","timestamp":1680307200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/royalsociety.org\/journals\/ethics-policies\/data-sharing-mining\/"}],"funder":[{"name":"AFM-T\u00e9l\u00e9thon","award":["17110"],"award-info":[{"award-number":["17110"]}]},{"DOI":"10.13039\/501100002915","name":"Fondation pour la Recherche M\u00e9dicale","doi-asserted-by":"crossref","award":["DEQ20130326534"],"award-info":[{"award-number":["DEQ20130326534"]}],"id":[{"id":"10.13039\/501100002915","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001665","name":"Agence Nationale de la Recherche","doi-asserted-by":"crossref","award":["ANR-17-CE12-0011-01"],"award-info":[{"award-number":["ANR-17-CE12-0011-01"]}],"id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["royalsocietypublishing.org"],"crossmark-restriction":true},"short-container-title":["Open Biol."],"published-print":{"date-parts":[[2023,4]]},"abstract":"<jats:p>\n                    Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant disease characterized by the progressive degeneration of specific muscles. OPMD is due to a mutation in the gene encoding poly(A) binding protein nuclear 1 (PABPN1) leading to a stretch of 11 to 18 alanines at N-terminus of the protein, instead of 10 alanines in the normal protein. This alanine tract extension induces the misfolding and aggregation of PABPN1 in muscle nuclei. Here, using\n                    <jats:italic>Drosophila<\/jats:italic>\n                    OPMD models, we show that the unfolded protein response (UPR) is activated in OPMD upon endoplasmic reticulum stress. Mutations in components of the PERK branch of the UPR reduce muscle degeneration and PABPN1 aggregation characteristic of the disease. We show that oral treatment of OPMD flies with Icerguastat (previously IFB-088), a Guanabenz acetate derivative that shows lower side effects, also decreases muscle degeneration and PABPN1 aggregation. Furthermore, the positive effect of Icerguastat depends on GADD34, a key component of the phosphatase complex in the PERK branch of the UPR. This study reveals a major contribution of the ER stress in OPMD pathogenesis and provides a proof-of-concept for Icerguastat interest in future pharmacological treatments of OPMD.\n                  <\/jats:p>","DOI":"10.1098\/rsob.230008","type":"journal-article","created":{"date-parts":[[2023,4,12]],"date-time":"2023-04-12T03:05:22Z","timestamp":1681268722000},"update-policy":"https:\/\/doi.org\/10.1098\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["The small compound Icerguastat reduces muscle defects in oculopharyngeal muscular dystrophy through the PERK pathway of the unfolded protein response"],"prefix":"10.1098","volume":"13","author":[{"given":"Rima","family":"Na\u00eft-Sa\u00efdi","sequence":"first","affiliation":[{"name":"Institute of Human Genetics, University of Montpellier, CNRS, Montpellier, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aymeric","family":"Chartier","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University of Montpellier, CNRS, Montpellier, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmanuelle","family":"Abgueguen","sequence":"additional","affiliation":[{"name":"InFlectis BioScience, Nantes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe","family":"Gu\u00e9dat","sequence":"additional","affiliation":[{"name":"InFlectis BioScience, Nantes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3731-6979","authenticated-orcid":true,"given":"Martine","family":"Simonelig","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University of Montpellier, CNRS, Montpellier, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"175","published-online":{"date-parts":[[2023,4,12]]},"reference":[{"key":"e_1_3_6_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2006.10.003"},{"key":"e_1_3_6_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.biocel.2006.01.016"},{"key":"e_1_3_6_4_2","doi-asserted-by":"publisher","DOI":"10.1089\/hum.2015.014"},{"key":"e_1_3_6_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng0298-164"},{"key":"e_1_3_6_6_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF00692226"},{"key":"e_1_3_6_7_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddg293"},{"key":"e_1_3_6_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/0304-3940(91)90230-Q"},{"key":"e_1_3_6_9_2","doi-asserted-by":"publisher","DOI":"10.1093\/oxfordjournals.hmg.a018924"},{"key":"e_1_3_6_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2004.10.019"},{"key":"e_1_3_6_11_2","doi-asserted-by":"publisher","DOI":"10.1017\/S0317167100002675"},{"key":"e_1_3_6_12_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkw703"},{"key":"e_1_3_6_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/0960-8966(93)90021-B"},{"key":"e_1_3_6_14_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0006418"},{"key":"e_1_3_6_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(91)90119-J"},{"key":"e_1_3_6_16_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/27.19.3771"},{"key":"e_1_3_6_17_2","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/cdg347"},{"key":"e_1_3_6_18_2","doi-asserted-by":"publisher","DOI":"10.1261\/rna.057026.116"},{"key":"e_1_3_6_19_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.018226"},{"key":"e_1_3_6_20_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gks655"},{"key":"e_1_3_6_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.03.022"},{"key":"e_1_3_6_22_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1003078"},{"key":"e_1_3_6_23_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1005610"},{"key":"e_1_3_6_24_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1003893"},{"key":"e_1_3_6_25_2","doi-asserted-by":"publisher","DOI":"10.4161\/rna.7.3.11649"},{"key":"e_1_3_6_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2016.09.025"},{"key":"e_1_3_6_27_2","doi-asserted-by":"publisher","DOI":"10.18632\/aging.100567"},{"key":"e_1_3_6_28_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddx206"},{"key":"e_1_3_6_29_2","first-page":"1137","article-title":"Anti-prion drugs targeting the protein folding activity of the ribosome reduce PABPN1 aggregation","volume":"18","author":"Bamia A","year":"2021","unstructured":"Bamia A et al. 2021 Anti-prion drugs targeting the protein folding activity of the ribosome reduce PABPN1 aggregation. Neurother. J. Am. Soc. Exp. Neurother. 18, 1137-1150. (doi:10.1007\/s13311-020-00992-6)","journal-title":"Neurother. J. Am. Soc. Exp. Neurother."},{"key":"e_1_3_6_30_2","doi-asserted-by":"publisher","DOI":"10.1002\/emmm.201000109"},{"key":"e_1_3_6_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ddtec.2012.07.002"},{"key":"e_1_3_6_32_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddi422"},{"key":"e_1_3_6_33_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm1242"},{"key":"e_1_3_6_34_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1010015"},{"key":"e_1_3_6_35_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1005092"},{"key":"e_1_3_6_36_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3270"},{"key":"e_1_3_6_37_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M200903200"},{"key":"e_1_3_6_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2014.01.012"},{"key":"e_1_3_6_39_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M806735200"},{"key":"e_1_3_6_40_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0400541101"},{"key":"e_1_3_6_41_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0809632106"},{"key":"e_1_3_6_42_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M301107200"},{"key":"e_1_3_6_43_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.153.5.1011"},{"key":"e_1_3_6_44_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1534-5807(02)00203-4"},{"key":"e_1_3_6_45_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(93)90648-A"},{"key":"e_1_3_6_46_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(93)90521-Q"},{"key":"e_1_3_6_47_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature07661"},{"key":"e_1_3_6_48_2","doi-asserted-by":"publisher","DOI":"10.1093\/jb\/mvh122"},{"key":"e_1_3_6_49_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(01)00611-0"},{"key":"e_1_3_6_50_2","doi-asserted-by":"publisher","DOI":"10.1038\/srep32117"},{"key":"e_1_3_6_51_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.biochi.2011.03.002"},{"key":"e_1_3_6_52_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0002174"},{"key":"e_1_3_6_53_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddz007"},{"key":"e_1_3_6_54_2","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb.3443"},{"key":"e_1_3_6_55_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaa4484"},{"key":"e_1_3_6_56_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.emboj.7601117"},{"key":"e_1_3_6_57_2","doi-asserted-by":"publisher","DOI":"10.1186\/1741-7007-6-1"},{"key":"e_1_3_6_58_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1108995"},{"key":"e_1_3_6_59_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.167213"},{"key":"e_1_3_6_60_2","doi-asserted-by":"publisher","DOI":"10.1242\/jeb.02202"},{"key":"e_1_3_6_61_2","first-page":"1406","article-title":"Coordinate regulation of eIF2\u03b1 phosphorylation by PPP1R15 and GCN2 is required during Drosophila development","volume":"126","author":"Malzer E","year":"2013","unstructured":"Malzer E, Szajewska-Skuta M, Dalton LE, Thomas SE, Hu N, Skaer H, Lomas DA, Crowther DC, Marciniak SJ. 2013 Coordinate regulation of eIF2\u03b1 phosphorylation by PPP1R15 and GCN2 is required during Drosophila development. J. Cell Sci. 126, 1406-1415. (doi:10.1242\/jcs.117614)","journal-title":"J. Cell Sci."},{"key":"e_1_3_6_62_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA118.002121"},{"key":"e_1_3_6_63_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1146361"},{"key":"e_1_3_6_64_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.0040374"},{"key":"e_1_3_6_65_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10495-013-0930-7"},{"key":"e_1_3_6_66_2","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2014.403"},{"key":"e_1_3_6_67_2","doi-asserted-by":"publisher","DOI":"10.1093\/genetics\/155.4.1711"},{"key":"e_1_3_6_68_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20122005"},{"key":"e_1_3_6_69_2","doi-asserted-by":"publisher","DOI":"10.1177\/1759091416642351"},{"key":"e_1_3_6_70_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddp101"},{"key":"e_1_3_6_71_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-018-0942-y"},{"key":"e_1_3_6_72_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2015.02.005"},{"key":"e_1_3_6_73_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2008.11.104"},{"key":"e_1_3_6_74_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1321845111"},{"key":"e_1_3_6_75_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2018.01.004"},{"key":"e_1_3_6_76_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2018.01.015"},{"key":"e_1_3_6_77_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1201396"},{"key":"e_1_3_6_78_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA118.002325"},{"key":"e_1_3_6_79_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.26109"},{"key":"e_1_3_6_80_2","doi-asserted-by":"publisher","DOI":"10.1021\/cn5001588"},{"key":"e_1_3_6_81_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-022-02838-y"},{"key":"e_1_3_6_82_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms15510"},{"key":"e_1_3_6_83_2","doi-asserted-by":"publisher","DOI":"10.1006\/excr.1994.1235"},{"key":"e_1_3_6_84_2","unstructured":"Na\u00eft-Sa\u00efdi R Chartier A Abgueguen E Gu\u00e9dat P Simonelig M. 2023 The small compound Icerguastat reduces muscle defects in oculopharyngeal muscular dystrophy through the PERK pathway of the unfolded protein response. Figshare. (doi:10.6084\/m9.figshare.c.6476390)"}],"container-title":["Open Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/royalsocietypublishing.org\/doi\/pdf\/10.1098\/rsob.230008","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/royalsocietypublishing.org\/doi\/full-xml\/10.1098\/rsob.230008","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/royalsocietypublishing.org\/doi\/pdf\/10.1098\/rsob.230008","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,4,12]],"date-time":"2023-04-12T03:05:37Z","timestamp":1681268737000},"score":1,"resource":{"primary":{"URL":"https:\/\/royalsocietypublishing.org\/doi\/10.1098\/rsob.230008"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4]]},"references-count":83,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2023,4]]}},"alternative-id":["10.1098\/rsob.230008"],"URL":"https:\/\/doi.org\/10.1098\/rsob.230008","relation":{"has-review":[{"id-type":"doi","id":"10.1098\/RSOB.230008\/v1\/decision1","asserted-by":"object"},{"id-type":"doi","id":"10.1098\/RSOB.230008\/v1\/review1","asserted-by":"object"},{"id-type":"doi","id":"10.1098\/RSOB.230008\/v2\/response1","asserted-by":"object"},{"id-type":"doi","id":"10.1098\/RSOB.230008\/v2\/decision1","asserted-by":"object"}]},"ISSN":["2046-2441"],"issn-type":[{"value":"2046-2441","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,4]]},"assertion":[{"value":"2023-01-11","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-03-07","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-04-12","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"230008"}}