{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T05:30:48Z","timestamp":1790487048551,"version":"4.1.0"},"reference-count":67,"publisher":"Oxford University Press (OUP)","issue":"17","license":[{"start":{"date-parts":[[2021,6,2]],"date-time":"2021-06-02T00:00:00Z","timestamp":1622592000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1-R35-NS116846-01"],"award-info":[{"award-number":["1-R35-NS116846-01"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000942","name":"Brain Foundation","doi-asserted-by":"publisher","award":["F2012(1)-101"],"award-info":[{"award-number":["F2012(1)-101"]}],"id":[{"id":"10.13039\/501100000942","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,8,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Fragile X-associated tremor and ataxia syndrome (FXTAS) is a late-onset, progressive neurodegenerative disorder characterized by tremors, ataxia and neuropsychological problems. This disease is quite common in the general population with approximately 20 million carriers worldwide. The risk of developing FXTAS increases dramatically with age, with about 45% of male carriers over the age of 50 being affected. FXTAS is caused by a CGG-repeat expansion (CGGexp) in the fragile X mental retardation 1 (FMR1) gene. CGGexp RNA is translated into the FMRpolyG protein by a mechanism called RAN translation. Although both gene and pathogenic trigger are known, no therapeutic interventions are available at this moment. Here, we present, for the first time, primary hippocampal neurons derived from the ubiquitous inducible mouse model which is used as a screening tool for targeted interventions. A promising candidate is the repeat binding, RAN translation blocking, small molecule 1a. Small molecule 1a shields the disease-causing CGGexp from being translated into the toxic FMRpolyG protein. Primary hippocampal neurons formed FMRpolyG-positive inclusions, and upon treatment with 1a, the numbers of FMRpolyG-positive inclusions are reduced. We also describe for the first time the formation of FMRpolyG-positive inclusions in the liver of this mouse model. Treatment with 1a reduced the insoluble FMRpolyG protein fraction in the liver but not the number of inclusions. Moreover, 1a treatment had a reducing effect on the number of Rad23b-positive inclusions and insoluble Rad23b protein levels. These data suggest that targeted small molecule therapy is effective in an FXTAS mouse model and has the potential to treat CGGexp-mediated diseases, including FXTAS.<\/jats:p>","DOI":"10.1093\/hmg\/ddab143","type":"journal-article","created":{"date-parts":[[2021,5,26]],"date-time":"2021-05-26T19:14:12Z","timestamp":1622056452000},"page":"1632-1648","source":"Crossref","is-referenced-by-count":15,"title":["Small molecule <i>1a<\/i> reduces FMRpolyG-mediated toxicity in <i>in vitro<\/i> and <i>in vivo<\/i> models for <i>FMR1<\/i> premutation"],"prefix":"10.1093","volume":"30","author":[{"given":"Saif N","family":"Haify","sequence":"first","affiliation":[{"name":"Department of Clinical Genetics, Erasmus MC, Rotterdam 3015 GD, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronald A M","family":"Buijsen","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Erasmus MC, Rotterdam 3015 GD, The Netherlands"},{"name":"Department of Human Genetics, LUMC, Leiden 2300 RC, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucas","family":"Verwegen","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Erasmus MC, Rotterdam 3015 GD, The Netherlands"},{"name":"Department of Cell Biology, Erasmus MC, Rotterdam 3015 GD, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lies-Anne W F M","family":"Severijnen","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Erasmus MC, Rotterdam 3015 GD, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen","family":"de Boer","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Erasmus MC, Rotterdam 3015 GD, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valerie","family":"Boumeester","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Erasmus MC, Rotterdam 3015 GD, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roos","family":"Monshouwer","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Erasmus MC, Rotterdam 3015 GD, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wang-Yong","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Scripps Research Institute, FL 33458, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael D","family":"Cameron","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Scripps Research Institute, FL 33458, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rob","family":"Willemsen","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Erasmus MC, Rotterdam 3015 GD, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew D","family":"Disney","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Scripps Research Institute, FL 33458, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renate K","family":"Hukema","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Erasmus MC, Rotterdam 3015 GD, The Netherlands"},{"name":"Department of Health Care Studies, Rotterdam University of Applied Sciences, Rotterdam 3015 GG, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,6,2]]},"reference":[{"key":"2021081712012599600_ref1","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1212\/WNL.57.1.127","article-title":"Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X","volume":"57","author":"Hagerman","year":"2001","journal-title":"Neurology"},{"key":"2021081712012599600_ref2","doi-asserted-by":"crossref","first-page":"830","DOI":"10.2310\/JIM.0b013e3181af59c4","article-title":"Fragile X-associated tremor\/ataxia syndrome: clinical phenotype, diagnosis, and treatment","volume":"57","author":"Leehey","year":"2009","journal-title":"J. Invest. Med."},{"key":"2021081712012599600_ref3","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1007\/978-1-4419-5805-1_3","volume-title":"The Fragile X-Associated Tremor Ataxia Syndrome (FXTAS)","author":"Grigsby","year":"2010"},{"key":"2021081712012599600_ref4","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1086\/374321","article-title":"Fragile X premutation tremor\/ataxia syndrome: molecular, clinical, and neuroimaging correlates","volume":"72","author":"Jacquemont","year":"2003","journal-title":"Am. J. Hum. Genet."},{"key":"2021081712012599600_ref5","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1186\/1866-1955-6-31","article-title":"Emerging topics in FXTAS","volume":"6","author":"Hall","year":"2014","journal-title":"J. Neurodev. Disord."},{"key":"2021081712012599600_ref6","first-page":"1757","article-title":"Fragile X premutation carriers: characteristic MR imaging findings of adult male patients with progressive cerebellar and cognitive dysfunction","volume":"23","author":"Brunberg","year":"2002","journal-title":"AJNR Am. J. Neuroradiol."},{"key":"2021081712012599600_ref7","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1093\/brain\/awh683","article-title":"Neuropathology of fragile X-associated tremor\/ataxia syndrome (FXTAS)","volume":"129","author":"Greco","year":"2006","journal-title":"Brain"},{"key":"2021081712012599600_ref8","doi-asserted-by":"crossref","first-page":"1760","DOI":"10.1093\/brain\/awf184","article-title":"Neuronal intranuclear inclusions in a new cerebellar tremor\/ataxia syndrome among fragile X carriers","volume":"125","author":"Greco","year":"2002","journal-title":"Brain"},{"key":"2021081712012599600_ref9","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1007\/s00401-011-0860-9","article-title":"Widespread non-central nervous system organ pathology in fragile X premutation carriers with fragile X-associated tremor\/ataxia syndrome and CGG knock-in mice","volume":"122","author":"Hunsaker","year":"2011","journal-title":"Acta Neuropathol."},{"key":"2021081712012599600_ref10","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1186\/s40478-014-0162-2","article-title":"FMRpolyG-positive inclusions in CNS and non-CNS organs of a fragile X premutation carrier with fragile X-associated tremor\/ataxia syndrome","volume":"2","author":"Buijsen","year":"2014","journal-title":"Acta Neuropathol. Commun."},{"key":"2021081712012599600_ref11","doi-asserted-by":"crossref","first-page":"1434","DOI":"10.1016\/j.juro.2006.11.097","article-title":"Testicular and pituitary inclusion formation in fragile X associated tremor\/ataxia syndrome","volume":"177","author":"Greco","year":"2007","journal-title":"J. Urol."},{"key":"2021081712012599600_ref12","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1111\/j.1440-1789.2008.00948.x","article-title":"Peripheral nervous system pathology in fragile X tremor\/ataxia syndrome (FXTAS)","volume":"29","author":"Gokden","year":"2009","journal-title":"Neuropathology"},{"key":"2021081712012599600_ref13","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1002\/mds.20753","article-title":"Parkinsonism, dysautonomia, and intranuclear inclusions in a fragile X carrier: a clinical-pathological study","volume":"21","author":"Louis","year":"2006","journal-title":"Mov. Disord."},{"key":"2021081712012599600_ref14","doi-asserted-by":"crossref","first-page":"e43","DOI":"10.1136\/jmg.2003.012518","article-title":"Intranuclear inclusions in neural cells with premutation alleles in fragile X associated tremor\/ataxia syndrome","volume":"41","author":"Tassone","year":"2004","journal-title":"J. Med. Genet."},{"key":"2021081712012599600_ref15","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1093\/humrep\/dev280","article-title":"Presence of inclusions positive for polyglycine containing protein, FMRpolyG, indicates that repeat-associated non-AUG translation plays a role in fragile X-associated primary ovarian insufficiency","volume":"31","author":"Buijsen","year":"2016","journal-title":"Hum. Reprod."},{"key":"2021081712012599600_ref16","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1016\/j.ejmg.2017.11.001","article-title":"Potential pathogenic mechanisms underlying fragile X tremor ataxia syndrome: RAN translation and\/or RNA gain-of-function?","volume":"61","author":"Boivin","year":"2018","journal-title":"Eur. J. Med. Genet."},{"key":"2021081712012599600_ref17","doi-asserted-by":"crossref","first-page":"1179","DOI":"10.1126\/science.252.5009.1179","article-title":"Fragile X genotype characterized by an unstable region of DNA","volume":"252","author":"Yu","year":"1991","journal-title":"Science"},{"key":"2021081712012599600_ref18","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1038\/jhg.2009.121","article-title":"Examination of FMR1 transcript and protein levels among 74 premutation carriers","volume":"55","author":"Peprah","year":"2010","journal-title":"J. Hum. 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Genet."},{"key":"2021081712012599600_ref21","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1001\/jama.291.4.460","article-title":"Penetrance of the fragile X-associated tremor\/ataxia syndrome in a premutation carrier population","volume":"291","author":"Jacquemont","year":"2004","journal-title":"JAMA"},{"key":"2021081712012599600_ref22","doi-asserted-by":"crossref","first-page":"1359","DOI":"10.1038\/ejhg.2009.51","article-title":"Penetrance of FMR1 premutation associated pathologies in fragile X syndrome families","volume":"17","author":"Rodriguez-Revenga","year":"2009","journal-title":"Eur. J. Hum. Genet."},{"key":"2021081712012599600_ref23","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1186\/1866-1955-6-23","article-title":"The multiple molecular facets of fragile X-associated tremor\/ataxia syndrome","volume":"6","author":"Sellier","year":"2014","journal-title":"J. Neurodev. 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Natl. Acad. Sci. U. S. A."},{"key":"2021081712012599600_ref29","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1016\/j.neuron.2013.03.026","article-title":"CGG repeat-associated translation mediates neurodegeneration in fragile X tremor ataxia syndrome","volume":"78","author":"Todd","year":"2013","journal-title":"Neuron"},{"key":"2021081712012599600_ref30","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1146\/annurev-neuro-070918-050405","article-title":"Repeat-associated non-ATG translation: molecular mechanisms and contribution to neurological disease","volume":"42","author":"Nguyen","year":"2019","journal-title":"Annu. Rev. Neurosci."},{"key":"2021081712012599600_ref31","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1016\/j.molcel.2016.02.034","article-title":"CGG repeat-associated non-AUG translation utilizes a cap-dependent scanning mechanism of initiation to produce toxic proteins","volume":"62","author":"Kearse","year":"2016","journal-title":"Mol. 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Mol. Genet."},{"key":"2021081712012599600_ref35","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1016\/j.neuron.2016.12.016","article-title":"Translation of expanded CGG repeats into FMRpolyG is pathogenic and may contribute to fragile X tremor ataxia syndrome","volume":"93","author":"Sellier","year":"2017","journal-title":"Neuron"},{"key":"2021081712012599600_ref36","doi-asserted-by":"crossref","first-page":"4948","DOI":"10.1093\/hmg\/ddv216","article-title":"Reversibility of neuropathology and motor deficits in an inducible mouse model for FXTAS","volume":"24","author":"Hukema","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"2021081712012599600_ref37","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1093\/hmg\/ddg114","article-title":"The FMR1 CGG repeat mouse displays ubiquitin-positive intranuclear neuronal inclusions; implications for the cerebellar tremor\/ataxia syndrome","volume":"12","author":"Willemsen","year":"2003","journal-title":"Hum. Mol. 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