{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T22:29:34Z","timestamp":1787005774586,"version":"build-2736575974"},"reference-count":15,"publisher":"National Academy of Sciences","issue":"31","license":[{"start":{"date-parts":[[2024,7,23]],"date-time":"2024-07-23T00:00:00Z","timestamp":1721692800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Government | Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["FDN-148423"],"award-info":[{"award-number":["FDN-148423"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["2020R1A6A3A03040141"],"award-info":[{"award-number":["2020R1A6A3A03040141"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000297","name":"FRAXA Research Foundation","doi-asserted-by":"publisher","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/100000297","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2024,7,30]]},"abstract":"<jats:p>\n                    Fragile X syndrome (FXS) is the most common genetic cause of autism spectrum disorder engendered by transcriptional silencing of the fragile X messenger ribonucleoprotein 1 (\n                    <jats:italic>FMR1<\/jats:italic>\n                    ) gene. Given the early onset of behavioral and molecular changes, it is imperative to know the optimal timing for therapeutic intervention. Case reports documented benefits of metformin treatment in FXS children between 2 and 14 y old. In this study, we administered metformin from birth to\n                    <jats:italic>\n                      Fmr1\n                      <jats:sup>\u2212\/y<\/jats:sup>\n                    <\/jats:italic>\n                    mice which corrected up-regulated mitogen-2 activated protein kinase\/extracellular signal-regulated kinase and mammalian\/mechanistic target of rapamycin complex 1 signaling pathways and specific synaptic mRNA-binding targets of FMRP. Metformin rescued increased number of calls in ultrasonic vocalization and repetitive behavior in\n                    <jats:italic>\n                      Fmr1\n                      <jats:sup>\u2212\/y<\/jats:sup>\n                    <\/jats:italic>\n                    mice. Our findings demonstrate that in mice, early-in-life metformin intervention is effective in treating FXS pathophysiology.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2407546121","type":"journal-article","created":{"date-parts":[[2024,7,23]],"date-time":"2024-07-23T13:48:47Z","timestamp":1721742527000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":7,"title":["Early metformin treatment: An effective approach for targeting fragile X syndrome pathophysiology"],"prefix":"10.1073","volume":"121","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8992-4992","authenticated-orcid":false,"given":"Jung-Hyun","family":"Choi","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Goodman Cancer Institute, McGill University, Montreal, QC H3A 1A3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6337-1656","authenticated-orcid":false,"given":"Laura","family":"Marsal-Garc\u00eda","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Goodman Cancer Institute, McGill University, Montreal, QC H3A 1A3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5417-2145","authenticated-orcid":false,"given":"Eve","family":"Peraldi","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Goodman Cancer Institute, McGill University, Montreal, QC H3A 1A3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caleb","family":"Walters","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Goodman Cancer Institute, McGill University, Montreal, QC H3A 1A3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziying","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Goodman Cancer Institute, McGill University, Montreal, QC H3A 1A3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5421-2581","authenticated-orcid":false,"given":"Ilse","family":"Gantois","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Goodman Cancer Institute, McGill University, Montreal, QC H3A 1A3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4707-8759","authenticated-orcid":false,"given":"Nahum","family":"Sonenberg","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Goodman Cancer Institute, McGill University, Montreal, QC H3A 1A3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2024,7,23]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2017.65"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1601-183X.2012.00768.x"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4335"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1002\/mgg3.956"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1111\/cge.13039"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1001\/jamapsychiatry.2016.1232"},{"key":"e_1_3_3_7_2","first-page":"100021","article-title":"Prepubertal metformin treatment in fragile X syndrome alleviated macroorchidism: A case study","volume":"3","author":"Protic D.","year":"2019","unstructured":"D. Protic, P. Kaluzhny, F. Tassone, R. J. Hagerman, Prepubertal metformin treatment in fragile X syndrome alleviated macroorchidism: A case study. Adv. Clin. Transl. Res. 3, 100021 (2019).","journal-title":"Adv. Clin. Transl. Res."},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1186\/s11689-020-09310-9"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3353"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41574-023-00833-4"},{"key":"e_1_3_3_11_2","unstructured":"ClinicalTrials.gov A Trial of Metformin in Individuals With Fragile X Syndrome (Met). ClinicalTrials.gov [NCBI]. https:\/\/classic.clinicaltrials.gov\/ct2\/show\/NCT03862950. Accessed 13 May 2024."},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1186\/s11689-016-9181-6"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3888-10.2010"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms19051544"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2019.11.023"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2407546121","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,7,23]],"date-time":"2024-07-23T13:50:21Z","timestamp":1721742621000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2407546121"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,7,23]]},"references-count":15,"journal-issue":{"issue":"31","published-print":{"date-parts":[[2024,7,30]]}},"alternative-id":["10.1073\/pnas.2407546121"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2407546121","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,7,23]]},"assertion":[{"value":"2024-04-18","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-06-24","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-07-23","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2407546121"}}