[{"publisher":"Institute of Science and Technology Austria","degree_awarded":"PhD","department":[{"_id":"GaNo"}],"status":"public","page":"88","month":"03","supervisor":[{"last_name":"Novarino","full_name":"Novarino, Gaia","first_name":"Gaia","orcid":"0000-0002-7673-7178","id":"3E57A680-F248-11E8-B48F-1D18A9856A87"}],"date_created":"2018-12-11T11:46:14Z","project":[{"name":"Transmembrane Transporters in Health and Disease","grant_number":"F03523","_id":"25473368-B435-11E9-9278-68D0E5697425","call_identifier":"FWF"}],"related_material":{"record":[{"relation":"part_of_dissertation","id":"1183","status":"public"}]},"language":[{"iso":"eng"}],"doi":"10.15479/AT:ISTA:th_992","ddc":["570","616"],"citation":{"ama":"Tarlungeanu D-C. The branched chain amino acids in autism spectrum disorders . 2018. doi:<a href=\"https://doi.org/10.15479/AT:ISTA:th_992\">10.15479/AT:ISTA:th_992</a>","apa":"Tarlungeanu, D.-C. (2018). <i>The branched chain amino acids in autism spectrum disorders </i>. Institute of Science and Technology Austria. <a href=\"https://doi.org/10.15479/AT:ISTA:th_992\">https://doi.org/10.15479/AT:ISTA:th_992</a>","short":"D.-C. Tarlungeanu, The Branched Chain Amino Acids in Autism Spectrum Disorders , Institute of Science and Technology Austria, 2018.","mla":"Tarlungeanu, Dora-Clara. <i>The Branched Chain Amino Acids in Autism Spectrum Disorders </i>. Institute of Science and Technology Austria, 2018, doi:<a href=\"https://doi.org/10.15479/AT:ISTA:th_992\">10.15479/AT:ISTA:th_992</a>.","chicago":"Tarlungeanu, Dora-Clara. “The Branched Chain Amino Acids in Autism Spectrum Disorders .” Institute of Science and Technology Austria, 2018. <a href=\"https://doi.org/10.15479/AT:ISTA:th_992\">https://doi.org/10.15479/AT:ISTA:th_992</a>.","ista":"Tarlungeanu D-C. 2018. The branched chain amino acids in autism spectrum disorders . Institute of Science and Technology Austria.","ieee":"D.-C. Tarlungeanu, “The branched chain amino acids in autism spectrum disorders ,” Institute of Science and Technology Austria, 2018."},"title":"The branched chain amino acids in autism spectrum disorders ","day":"01","type":"dissertation","author":[{"id":"2ABCE612-F248-11E8-B48F-1D18A9856A87","first_name":"Dora-Clara","full_name":"Tarlungeanu, Dora-Clara","last_name":"Tarlungeanu"}],"alternative_title":["ISTA Thesis"],"publication_status":"published","oa":1,"file_date_updated":"2021-02-11T23:30:15Z","tmp":{"legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","image":"/images/cc_by.png","short":"CC BY (4.0)"},"pubrep_id":"992","article_processing_charge":"No","file":[{"checksum":"9f5231c96e0ad945040841a8630232da","date_updated":"2021-02-11T23:30:15Z","access_level":"closed","file_name":"2018_Thesis_Tarlungeanu_source.docx","creator":"dernst","file_size":43684035,"date_created":"2019-04-05T09:19:17Z","embargo_to":"open_access","content_type":"application/vnd.openxmlformats-officedocument.wordprocessingml.document","relation":"source_file","file_id":"6217"},{"checksum":"0c33c370aa2010df5c552db57a6d01e9","date_updated":"2021-02-11T11:17:16Z","access_level":"open_access","file_name":"2018_Thesis_Tarlungeanu.pdf","creator":"dernst","file_size":30511532,"embargo":"2018-03-15","date_created":"2019-04-05T09:19:17Z","content_type":"application/pdf","file_id":"6218","relation":"main_file"}],"_id":"395","date_published":"2018-03-01T00:00:00Z","abstract":[{"text":"Autism spectrum disorders (ASD) are a group of genetic disorders often overlapping with other neurological conditions. Despite the remarkable number of scientific breakthroughs of the last 100 years, the treatment of neurodevelopmental disorders (e.g. autism spectrum disorder, intellectual disability, epilepsy) remains a great challenge. Recent advancements in geno mics, like whole-exome or whole-genome sequencing, have enabled scientists to identify numerous mutations underlying neurodevelopmental disorders. Given the few hundred risk genes that were discovered, the etiological variability and the heterogeneous phenotypic outcomes, the need for genotype -along with phenotype- based diagnosis of individual patients becomes a requisite. Driven by this rationale, in a previous study our group described mutations, identified via whole - exome sequencing, in the gene BCKDK – encoding for a key regulator of branched chain amin o acid (BCAA) catabolism - as a cause of ASD. Following up on the role of BCAAs, in the study described here we show that the solute carrier transporter 7a5 (SLC7A5), a large neutral amino acid transporter localized mainly at the blood brain barrier (BBB), has an essential role in maintaining normal levels of brain BCAAs. In mice, deletion of Slc7a5 from the endothelial cells of the BBB leads to atypical brain amino acid profile, abnormal mRNA translation and severe neurolo gical abnormalities. Additionally, deletion of Slc7a5 from the neural progenitor cell population leads to microcephaly. Interestingly, we demonstrate that BCAA intracerebroventricular administration ameliorates abnormal behaviors in adult mutant mice. Furthermore, whole - exome sequencing of patients diagnosed with neurological dis o r ders helped us identify several patients with autistic traits, microcephaly and motor delay carrying deleterious homozygous mutations in the SLC7A5 gene. In conclusion, our data elucidate a neurological syndrome defined by SLC7A5 mutations and support an essential role for t he BCAA s in human bra in function. Together with r ecent studies (described in chapter two) that have successfully made the transition into clinical practice, our findings on the role of B CAAs might have a crucial impact on the development of novel individualized therapeutic strategies for ASD. ","lang":"eng"}],"date_updated":"2023-09-07T12:38:59Z","user_id":"c635000d-4b10-11ee-a964-aac5a93f6ac1","acknowledged_ssus":[{"_id":"PreCl"},{"_id":"EM-Fac"},{"_id":"Bio"}],"publication_identifier":{"issn":["2663-337X"]},"publist_id":"7434","year":"2018","oa_version":"Published Version","has_accepted_license":"1"},{"department":[{"_id":"GaNo"}],"quality_controlled":"1","publication":"Translational Anatomy and Cell Biology of Autism Spectrum Disorder","status":"public","intvolume":"       224","publisher":"Springer","month":"05","series_title":"Advances in Anatomy Embryology and Cell Biology","date_created":"2018-12-11T11:47:37Z","page":"189 - 211","language":[{"iso":"eng"}],"doi":"10.1007/978-3-319-52498-6_10","project":[{"grant_number":"F03523","name":"Transmembrane Transporters in Health and Disease","call_identifier":"FWF","_id":"25473368-B435-11E9-9278-68D0E5697425"}],"day":"28","alternative_title":["ADVSANAT"],"type":"book_chapter","author":[{"full_name":"Schroeder, Jan","first_name":"Jan","last_name":"Schroeder"},{"id":"37A40D7E-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0002-7370-5293","last_name":"Deliu","full_name":"Deliu, Elena","first_name":"Elena"},{"first_name":"Gaia","full_name":"Novarino, Gaia","last_name":"Novarino","id":"3E57A680-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0002-7673-7178"},{"last_name":"Schmeisser","full_name":"Schmeisser, Michael","first_name":"Michael"}],"citation":{"ama":"Schroeder J, Deliu E, Novarino G, Schmeisser M. Genetic and pharmacological reversibility of phenotypes in mouse models of autism spectrum disorder. In: Schmeisser M, Boekers T, eds. <i>Translational Anatomy and Cell Biology of Autism Spectrum Disorder</i>. Vol 224. Advances in Anatomy Embryology and Cell Biology. Springer; 2017:189-211. doi:<a href=\"https://doi.org/10.1007/978-3-319-52498-6_10\">10.1007/978-3-319-52498-6_10</a>","apa":"Schroeder, J., Deliu, E., Novarino, G., &#38; Schmeisser, M. (2017). Genetic and pharmacological reversibility of phenotypes in mouse models of autism spectrum disorder. In M. Schmeisser &#38; T. Boekers (Eds.), <i>Translational Anatomy and Cell Biology of Autism Spectrum Disorder</i> (Vol. 224, pp. 189–211). Springer. <a href=\"https://doi.org/10.1007/978-3-319-52498-6_10\">https://doi.org/10.1007/978-3-319-52498-6_10</a>","short":"J. Schroeder, E. Deliu, G. Novarino, M. Schmeisser, in:, M. Schmeisser, T. Boekers (Eds.), Translational Anatomy and Cell Biology of Autism Spectrum Disorder, Springer, 2017, pp. 189–211.","mla":"Schroeder, Jan, et al. “Genetic and Pharmacological Reversibility of Phenotypes in Mouse Models of Autism Spectrum Disorder.” <i>Translational Anatomy and Cell Biology of Autism Spectrum Disorder</i>, edited by Michael Schmeisser and Tobias Boekers, vol. 224, Springer, 2017, pp. 189–211, doi:<a href=\"https://doi.org/10.1007/978-3-319-52498-6_10\">10.1007/978-3-319-52498-6_10</a>.","chicago":"Schroeder, Jan, Elena Deliu, Gaia Novarino, and Michael Schmeisser. “Genetic and Pharmacological Reversibility of Phenotypes in Mouse Models of Autism Spectrum Disorder.” In <i>Translational Anatomy and Cell Biology of Autism Spectrum Disorder</i>, edited by Michael Schmeisser and Tobias Boekers, 224:189–211. Advances in Anatomy Embryology and Cell Biology. Springer, 2017. <a href=\"https://doi.org/10.1007/978-3-319-52498-6_10\">https://doi.org/10.1007/978-3-319-52498-6_10</a>.","ista":"Schroeder J, Deliu E, Novarino G, Schmeisser M. 2017.Genetic and pharmacological reversibility of phenotypes in mouse models of autism spectrum disorder. In: Translational Anatomy and Cell Biology of Autism Spectrum Disorder. ADVSANAT, vol. 224, 189–211.","ieee":"J. Schroeder, E. Deliu, G. Novarino, and M. Schmeisser, “Genetic and pharmacological reversibility of phenotypes in mouse models of autism spectrum disorder,” in <i>Translational Anatomy and Cell Biology of Autism Spectrum Disorder</i>, vol. 224, M. Schmeisser and T. Boekers, Eds. Springer, 2017, pp. 189–211."},"title":"Genetic and pharmacological reversibility of phenotypes in mouse models of autism spectrum disorder","volume":224,"publication_status":"published","abstract":[{"text":"As autism spectrum disorder (ASD) is largely regarded as a neurodevelopmental condition, long-time consensus was that its hallmark features are irreversible. However, several studies from recent years using defined mouse models of ASD have provided clear evidence that in mice neurobiological and behavioural alterations can be ameliorated or even reversed by genetic restoration or pharmacological treatment either before or after symptom onset. Here, we review findings on genetic and pharmacological reversibility of phenotypes in mouse models of ASD. Our review should give a comprehensive overview on both aspects and encourage future studies to better understand the underlying molecular mechanisms that might be translatable from animals to humans.","lang":"eng"}],"_id":"634","date_published":"2017-05-28T00:00:00Z","date_updated":"2021-01-12T08:07:08Z","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","scopus_import":1,"publication_identifier":{"eisbn":["978-3-319-52498-6"]},"publist_id":"7156","year":"2017","oa_version":"None","editor":[{"last_name":"Schmeisser","full_name":"Schmeisser, Michael","first_name":"Michael"},{"last_name":"Boekers","full_name":"Boekers, Tobias","first_name":"Tobias"}]},{"month":"12","date_created":"2018-12-11T11:50:35Z","page":"1481 - 1494","publication":"Cell","quality_controlled":"1","department":[{"_id":"GaNo"}],"status":"public","intvolume":"       167","publisher":"Cell Press","day":"01","author":[{"full_name":"Tarlungeanu, Dora-Clara","first_name":"Dora-Clara","last_name":"Tarlungeanu","id":"2ABCE612-F248-11E8-B48F-1D18A9856A87"},{"last_name":"Deliu","full_name":"Deliu, Elena","first_name":"Elena","orcid":"0000-0002-7370-5293","id":"37A40D7E-F248-11E8-B48F-1D18A9856A87"},{"id":"4C66542E-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0002-9033-9096","full_name":"Dotter, Christoph","first_name":"Christoph","last_name":"Dotter"},{"last_name":"Kara","full_name":"Kara, Majdi","first_name":"Majdi"},{"last_name":"Janiesch","first_name":"Philipp","full_name":"Janiesch, Philipp"},{"full_name":"Scalise, Mariafrancesca","first_name":"Mariafrancesca","last_name":"Scalise"},{"last_name":"Galluccio","full_name":"Galluccio, Michele","first_name":"Michele"},{"last_name":"Tesulov","first_name":"Mateja","full_name":"Tesulov, Mateja"},{"id":"3F4D1282-F248-11E8-B48F-1D18A9856A87","last_name":"Morelli","first_name":"Emanuela","full_name":"Morelli, Emanuela"},{"last_name":"Sönmez","first_name":"Fatma","full_name":"Sönmez, Fatma"},{"first_name":"Kaya","full_name":"Bilgüvar, Kaya","last_name":"Bilgüvar"},{"last_name":"Ohgaki","first_name":"Ryuichi","full_name":"Ohgaki, Ryuichi"},{"first_name":"Yoshikatsu","full_name":"Kanai, Yoshikatsu","last_name":"Kanai"},{"full_name":"Johansen, Anide","first_name":"Anide","last_name":"Johansen"},{"first_name":"Seham","full_name":"Esharif, Seham","last_name":"Esharif"},{"last_name":"Ben Omran","full_name":"Ben Omran, Tawfeg","first_name":"Tawfeg"},{"last_name":"Topcu","full_name":"Topcu, Meral","first_name":"Meral"},{"first_name":"Avner","full_name":"Schlessinger, Avner","last_name":"Schlessinger"},{"last_name":"Indiveri","full_name":"Indiveri, Cesare","first_name":"Cesare"},{"last_name":"Duncan","full_name":"Duncan, Kent","first_name":"Kent"},{"full_name":"Caglayan, Ahmet","first_name":"Ahmet","last_name":"Caglayan"},{"last_name":"Günel","full_name":"Günel, Murat","first_name":"Murat"},{"last_name":"Gleeson","first_name":"Joseph","full_name":"Gleeson, Joseph"},{"last_name":"Novarino","full_name":"Novarino, Gaia","first_name":"Gaia","orcid":"0000-0002-7673-7178","id":"3E57A680-F248-11E8-B48F-1D18A9856A87"}],"type":"journal_article","citation":{"short":"D.-C. Tarlungeanu, E. Deliu, C. Dotter, M. Kara, P. Janiesch, M. Scalise, M. Galluccio, M. Tesulov, E. Morelli, F. Sönmez, K. Bilgüvar, R. Ohgaki, Y. Kanai, A. Johansen, S. Esharif, T. Ben Omran, M. Topcu, A. Schlessinger, C. Indiveri, K. Duncan, A. Caglayan, M. Günel, J. Gleeson, G. Novarino, Cell 167 (2016) 1481–1494.","apa":"Tarlungeanu, D.-C., Deliu, E., Dotter, C., Kara, M., Janiesch, P., Scalise, M., … Novarino, G. (2016). Impaired amino acid transport at the blood brain barrier is a cause of autism spectrum disorder. <i>Cell</i>. Cell Press. <a href=\"https://doi.org/10.1016/j.cell.2016.11.013\">https://doi.org/10.1016/j.cell.2016.11.013</a>","ama":"Tarlungeanu D-C, Deliu E, Dotter C, et al. Impaired amino acid transport at the blood brain barrier is a cause of autism spectrum disorder. <i>Cell</i>. 2016;167(6):1481-1494. doi:<a href=\"https://doi.org/10.1016/j.cell.2016.11.013\">10.1016/j.cell.2016.11.013</a>","ieee":"D.-C. Tarlungeanu <i>et al.</i>, “Impaired amino acid transport at the blood brain barrier is a cause of autism spectrum disorder,” <i>Cell</i>, vol. 167, no. 6. Cell Press, pp. 1481–1494, 2016.","ista":"Tarlungeanu D-C, Deliu E, Dotter C, Kara M, Janiesch P, Scalise M, Galluccio M, Tesulov M, Morelli E, Sönmez F, Bilgüvar K, Ohgaki R, Kanai Y, Johansen A, Esharif S, Ben Omran T, Topcu M, Schlessinger A, Indiveri C, Duncan K, Caglayan A, Günel M, Gleeson J, Novarino G. 2016. Impaired amino acid transport at the blood brain barrier is a cause of autism spectrum disorder. Cell. 167(6), 1481–1494.","chicago":"Tarlungeanu, Dora-Clara, Elena Deliu, Christoph Dotter, Majdi Kara, Philipp Janiesch, Mariafrancesca Scalise, Michele Galluccio, et al. “Impaired Amino Acid Transport at the Blood Brain Barrier Is a Cause of Autism Spectrum Disorder.” <i>Cell</i>. Cell Press, 2016. <a href=\"https://doi.org/10.1016/j.cell.2016.11.013\">https://doi.org/10.1016/j.cell.2016.11.013</a>.","mla":"Tarlungeanu, Dora-Clara, et al. “Impaired Amino Acid Transport at the Blood Brain Barrier Is a Cause of Autism Spectrum Disorder.” <i>Cell</i>, vol. 167, no. 6, Cell Press, 2016, pp. 1481–94, doi:<a href=\"https://doi.org/10.1016/j.cell.2016.11.013\">10.1016/j.cell.2016.11.013</a>."},"title":"Impaired amino acid transport at the blood brain barrier is a cause of autism spectrum disorder","language":[{"iso":"eng"}],"ddc":["576","616"],"doi":"10.1016/j.cell.2016.11.013","project":[{"grant_number":"F03523","name":"Transmembrane Transporters in Health and Disease","call_identifier":"FWF","_id":"25473368-B435-11E9-9278-68D0E5697425"}],"related_material":{"record":[{"relation":"dissertation_contains","id":"395","status":"public"}]},"acknowledgement":"This work was supported by NICHD (P01HD070494) and SFARI (grant 275275) to J.G.G., and FWF (SFB35_3523) to G.N.\r\nWe thank A.C. Manzano, Mike Liu, and F. Marr for technical assistance, and R. Shigemoto and the IST Austria Electron Microscopy (EM) Facility for assistance. We acknowledge support from CIDR for genome-wide SNP analysis (X01HG008823) and Broad Institute Center for Mendelian Disorders (UM1HG008900 to D. MacArthur), the Yale Center for Mendelian Disorders (U54HG006504 to M.G.), the Gregory M. Kiez and Mehmet Kutman Foundation (M.G.), Italian Ministry of Instruction University and Research (PON01_00937 to C.I.), and NIH (R01-GM108911 to A.S.). This work was supported by NICHD (P01HD070494) and SFARI (grant 275275) to J.G.G., and FWF (SFB35_3523) to G.N.\r\n\r\n#EMFacility","file":[{"relation":"main_file","file_id":"5030","content_type":"application/pdf","date_created":"2018-12-12T10:13:44Z","creator":"system","file_size":73907957,"file_name":"IST-2017-771-v1+1_Tarlungeanu_et_al._Final_edited.pdf","access_level":"open_access","date_updated":"2020-07-14T12:44:37Z","checksum":"7fe01ab12a6610d3db421e0136db2f77"}],"date_published":"2016-12-01T00:00:00Z","_id":"1183","abstract":[{"lang":"eng","text":"Autism spectrum disorders (ASD) are a group of genetic disorders often overlapping with other neurological conditions. We previously described abnormalities in the branched-chain amino acid (BCAA) catabolic pathway as a cause of ASD. Here, we show that the solute carrier transporter 7a5 (SLC7A5), a large neutral amino acid transporter localized at the blood brain barrier (BBB), has an essential role in maintaining normal levels of brain BCAAs. In mice, deletion of Slc7a5 from the endothelial cells of the BBB leads to atypical brain amino acid profile, abnormal mRNA translation, and severe neurological abnormalities. Furthermore, we identified several patients with autistic traits and motor delay carrying deleterious homozygous mutations in the SLC7A5 gene. Finally, we demonstrate that BCAA intracerebroventricular administration ameliorates abnormal behaviors in adult mutant mice. Our data elucidate a neurological syndrome defined by SLC7A5 mutations and support an essential role for the BCAA in human brain function."}],"article_processing_charge":"No","issue":"6","file_date_updated":"2020-07-14T12:44:37Z","pubrep_id":"771","volume":167,"publication_status":"published","oa":1,"article_type":"original","publist_id":"6170","year":"2016","oa_version":"Submitted Version","has_accepted_license":"1","scopus_import":"1","date_updated":"2024-03-25T23:30:07Z","user_id":"8b945eb4-e2f2-11eb-945a-df72226e66a9"}]