{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T15:40:31Z","timestamp":1793029231975,"version":"4.5.0"},"reference-count":50,"publisher":"National Academy of Sciences","issue":"14","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2013,4,2]]},"abstract":"<jats:p>\n                    Fragile X syndrome (FXS) is the most common inherited form of autism and intellectual disability and is caused by the silencing of a single gene, fragile X mental retardation 1 (\n                    <jats:italic>Fmr1<\/jats:italic>\n                    ). The\n                    <jats:italic>Fmr1<\/jats:italic>\n                    KO mouse displays phenotypes similar to symptoms in the human condition\u2014including hyperactivity, repetitive behaviors, and seizures\u2014as well as analogous abnormalities in the density of dendritic spines. Here we take a hypothesis-driven, mechanism-based approach to the search for an effective therapy for FXS. We hypothesize that a treatment that rescues the dendritic spine defect in\n                    <jats:italic>Fmr1<\/jats:italic>\n                    KO mice may also ameliorate autism-like behavioral symptoms. Thus, we targeted a protein that regulates spines through modulation of actin cytoskeleton dynamics: p21-activated kinase (PAK). Our results demonstrate that a potent small molecule inhibitor of group I PAKs reverses dendritic spine phenotypes in\n                    <jats:italic>Fmr1<\/jats:italic>\n                    KO mice. Moreover, this PAK inhibitor\u2014which we call FRAX486\u2014also rescues seizures and behavioral abnormalities such as hyperactivity and repetitive movements, thereby supporting the hypothesis that a drug treatment that reverses the spine abnormalities can also treat neurological and behavioral symptoms. Finally, a single administration of FRAX486 is sufficient to rescue all of these phenotypes in adult\n                    <jats:italic>Fmr1<\/jats:italic>\n                    KO mice, demonstrating the potential for rapid, postdiagnostic therapy in adults with FXS.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1219383110","type":"journal-article","created":{"date-parts":[[2013,3,19]],"date-time":"2013-03-19T03:06:17Z","timestamp":1363662377000},"page":"5671-5676","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":222,"title":["Rescue of fragile X syndrome phenotypes in\n                    <i>Fmr1<\/i>\n                    KO mice by the small-molecule PAK inhibitor FRAX486"],"prefix":"10.1073","volume":"110","author":[{"given":"Bridget M.","family":"Dolan","sequence":"first","affiliation":[{"name":"Picower Institute for Learning and Memory, RIKEN-MIT Center for Neural Circuit Genetics, Department of Biology and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergio G.","family":"Duron","sequence":"additional","affiliation":[{"name":"Afraxis, Inc., La Jolla, CA 92037;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Campbell","sequence":"additional","affiliation":[{"name":"Afraxis, Inc., La Jolla, CA 92037;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benedikt","family":"Vollrath","sequence":"additional","affiliation":[{"name":"Afraxis, Inc., La Jolla, CA 92037;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B. S. Shankaranarayana","family":"Rao","sequence":"additional","affiliation":[{"name":"Department of Neurophysiology, National Institute of Mental Health and Neuro Sciences, Bangalore 560029, India; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui-Yeon","family":"Ko","sequence":"additional","affiliation":[{"name":"Department of Physiology, Seoul National University School of Dentistry, Seoul 110-749, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory G.","family":"Lin","sequence":"additional","affiliation":[{"name":"Picower Institute for Learning and Memory, RIKEN-MIT Center for Neural Circuit Genetics, Department of Biology and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arvind","family":"Govindarajan","sequence":"additional","affiliation":[{"name":"Picower Institute for Learning and Memory, RIKEN-MIT Center for Neural Circuit Genetics, Department of Biology and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Se-Young","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Physiology, Seoul National University School of Dentistry, Seoul 110-749, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susumu","family":"Tonegawa","sequence":"additional","affiliation":[{"name":"Picower Institute for Learning and Memory, RIKEN-MIT Center for Neural Circuit Genetics, Department of Biology and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2013,3,18]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2010-2989"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2011-0427"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2008-0317"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrg2346"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(91)90397-H"},{"key":"e_1_3_3_6_2","first-page":"23","article-title":"Fmr1 knockout mice: A model to study fragile X mental retardation","volume":"78","author":"The Dutch-Belgian Fragile X Consortium","year":"1994","unstructured":"; The Dutch-Belgian Fragile X Consortium, Fmr1 knockout mice: A model to study fragile X mental retardation. 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