Generation of a Novel Rat Model of Angelman Syndrome with a Complete Ube3a Gene Deletion / Andie DODGE in Autism Research, 13-3 (March 2020)  

Public ISBD [article]  inAutism Research > 13-3 (March 2020) . - p.397-409 Titre : Generation of a Novel Rat Model of Angelman Syndrome with a Complete Ube3a Gene Deletion Type de document : Texte imprimé et/ou numérique Auteurs : Andie DODGE, Auteur ; Melinda M. PETERS, Auteur ; Hayden E. GREENE, Auteur ; Clifton DIETRICK, Auteur ; Robert BOTELHO, Auteur ; Diana CHUNG, Auteur ; Jonathan WILLMAN, Auteur ; Austin W NENNINGER, Auteur ; Stephanie CIARLONE, Auteur ; Siddharth G. KAMATH, Auteur ; Pavel HOUDEK, Auteur ; Alena SUMOVA, Auteur ; Anne E. ANDERSON, Auteur ; Scott V. DINDOT, Auteur ; Elizabeth L. BERG, Auteur ; Henriette O'GEEN, Auteur ; David J. SEGAL, Auteur ; Jill L. SILVERMAN, Auteur ; Edwin J. WEEBER, Auteur ; Kevin R. NASH, Auteur Article en page(s) : p.397-409 Langues : Anglais (eng) Mots-clés : Angelman syndrome  E6ap  Ube3a  cognitive deficits  rat model Index. décimale : PER Périodiques Résumé : Angelman syndrome (AS) is a rare genetic disorder characterized by severe intellectual disability, seizures, lack of speech, and ataxia. The gene responsible for AS was identified as Ube3a and it encodes for E6AP, an E3 ubiquitin ligase. Currently, there is very little known about E6AP's mechanism of action in vivo or how the lack of this protein in neurons may contribute to the AS phenotype. Elucidating the mechanistic action of E6AP would enhance our understanding of AS and drive current research into new avenues that could lead to novel therapeutic approaches that target E6AP's various functions. To facilitate the study of AS, we have generated a novel rat model in which we deleted the rat Ube3a gene using CRISPR. The AS rat phenotypically mirrors human AS with loss of Ube3a expression in the brain and deficits in motor coordination as well as learning and memory. This model offers a new avenue for the study of AS. Autism Res 2020, 13: 397-409. (c) 2020 International Society for Autism Research,Wiley Periodicals, Inc. LAY SUMMARY: Angelman syndrome (AS) is a rare genetic disorder characterized by severe intellectual disability, seizures, difficulty speaking, and ataxia. The gene responsible for AS was identified as UBE3A, yet very little is known about its function in vivo or how the lack of this protein in neurons may contribute to the AS phenotype. To facilitate the study of AS, we have generated a novel rat model in which we deleted the rat Ube3a gene using CRISPR. The AS rat mirrors human AS with loss of Ube3a expression in the brain and deficits in motor coordination as well as learning and memory. This model offers a new avenue for the study of AS. En ligne : http://dx.doi.org/10.1002/aur.2267 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=421 [article] Generation of a Novel Rat Model of Angelman Syndrome with a Complete Ube3a Gene Deletion [Texte imprimé et/ou numérique] / Andie DODGE, Auteur ; Melinda M. PETERS, Auteur ; Hayden E. GREENE, Auteur ; Clifton DIETRICK, Auteur ; Robert BOTELHO, Auteur ; Diana CHUNG, Auteur ; Jonathan WILLMAN, Auteur ; Austin W NENNINGER, Auteur ; Stephanie CIARLONE, Auteur ; Siddharth G. KAMATH, Auteur ; Pavel HOUDEK, Auteur ; Alena SUMOVA, Auteur ; Anne E. ANDERSON, Auteur ; Scott V. DINDOT, Auteur ; Elizabeth L. BERG, Auteur ; Henriette O'GEEN, Auteur ; David J. SEGAL, Auteur ; Jill L. SILVERMAN, Auteur ; Edwin J. WEEBER, Auteur ; Kevin R. NASH, Auteur . - p.397-409. Langues : Anglais (eng) in Autism Research > 13-3 (March 2020) . - p.397-409 Mots-clés : Angelman syndrome  E6ap  Ube3a  cognitive deficits  rat model Index. décimale : PER Périodiques Résumé : Angelman syndrome (AS) is a rare genetic disorder characterized by severe intellectual disability, seizures, lack of speech, and ataxia. The gene responsible for AS was identified as Ube3a and it encodes for E6AP, an E3 ubiquitin ligase. Currently, there is very little known about E6AP's mechanism of action in vivo or how the lack of this protein in neurons may contribute to the AS phenotype. Elucidating the mechanistic action of E6AP would enhance our understanding of AS and drive current research into new avenues that could lead to novel therapeutic approaches that target E6AP's various functions. To facilitate the study of AS, we have generated a novel rat model in which we deleted the rat Ube3a gene using CRISPR. The AS rat phenotypically mirrors human AS with loss of Ube3a expression in the brain and deficits in motor coordination as well as learning and memory. This model offers a new avenue for the study of AS. Autism Res 2020, 13: 397-409. (c) 2020 International Society for Autism Research,Wiley Periodicals, Inc. LAY SUMMARY: Angelman syndrome (AS) is a rare genetic disorder characterized by severe intellectual disability, seizures, difficulty speaking, and ataxia. The gene responsible for AS was identified as UBE3A, yet very little is known about its function in vivo or how the lack of this protein in neurons may contribute to the AS phenotype. To facilitate the study of AS, we have generated a novel rat model in which we deleted the rat Ube3a gene using CRISPR. The AS rat mirrors human AS with loss of Ube3a expression in the brain and deficits in motor coordination as well as learning and memory. This model offers a new avenue for the study of AS. En ligne : http://dx.doi.org/10.1002/aur.2267 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=421

Identification of UBE3A Protein in CSF and Extracellular Space of the Hippocampus Suggest a Potential Novel Function in Synaptic Plasticity / Andie DODGE in Autism Research, 14-4 (April 2021)  

Public ISBD [article]  inAutism Research > 14-4 (April 2021) . - p.645-655 Titre : Identification of UBE3A Protein in CSF and Extracellular Space of the Hippocampus Suggest a Potential Novel Function in Synaptic Plasticity Type de document : Texte imprimé et/ou numérique Auteurs : Andie DODGE, Auteur ; Jonathan WILLMAN, Auteur ; Matthew WILLMAN, Auteur ; Austin W NENNINGER, Auteur ; Nicole K. MORRILL, Auteur ; Kristina LAMENS, Auteur ; Hayden GREENE, Auteur ; Edwin J. WEEBER, Auteur ; Kevin R. NASH, Auteur Article en page(s) : p.645-655 Langues : Anglais (eng) Mots-clés : Angelman syndrome  Csf  E6ap  Ube3a  rat model Index. décimale : PER Périodiques Résumé : Disruptions to the maternally inherited allele UBE3A, encoding for an E3 ubiquitin ligase, leads to the manifestation of Angelman Syndrome (AS). While this disorder is rare, the symptoms are severe and lifelong including but not limited to: intractable seizures, abnormal EEG's, ataxic gait, lack of speech, and most notably an abnormally happy demeanor with easily provoked laughter. Currently, little is known about the neurophysiological underpinnings of UBE3A leading to such globally severe phenotypes. Utilizing the newest AS rat model, comprised of a full UBE3A deletion, we aimed to elucidate novel mechanistic actions and potential therapeutic targets. This report demonstrates for the first time that catalytically active UBE3A protein is detectable within cerebrospinal fluid (CSF) of wild type rats but distinctly absent in AS rat CSF. Microdialysis within the rat hippocampus also showed that UBE3A protein is located in the interstitial fluid of wild type rat brains but absent in AS animals. This protein maintains catalytic activity and appears to be regulated in a dynamic activity-dependent manner. LAY SUMMARY: Angelman syndrome (AS) is a rare genetic disorder caused by the loss of the UBE3A gene within the central nervous system. Although we have identified the gene responsible for AS, we still have a long way to go to fully understand its function in vivo. Here we report that UBE3A is present within normal cerebrospinal fluid (CSF) but distinctly absent in AS CSF. Furthermore, we demonstrate that UBE3A is secreted and that this may occur in a dynamic activity-dependent fashion. Extracellular UBE3A maintained its ubiquitinating activity, thus suggesting that UBE3A may have a novel role outside of neurons. Autism Res 2021, 14: 645-655. © 2021 International Society for Autism Research and Wiley Periodicals LLC. En ligne : http://dx.doi.org/10.1002/aur.2475 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=443 [article] Identification of UBE3A Protein in CSF and Extracellular Space of the Hippocampus Suggest a Potential Novel Function in Synaptic Plasticity [Texte imprimé et/ou numérique] / Andie DODGE, Auteur ; Jonathan WILLMAN, Auteur ; Matthew WILLMAN, Auteur ; Austin W NENNINGER, Auteur ; Nicole K. MORRILL, Auteur ; Kristina LAMENS, Auteur ; Hayden GREENE, Auteur ; Edwin J. WEEBER, Auteur ; Kevin R. NASH, Auteur . - p.645-655. Langues : Anglais (eng) in Autism Research > 14-4 (April 2021) . - p.645-655 Mots-clés : Angelman syndrome  Csf  E6ap  Ube3a  rat model Index. décimale : PER Périodiques Résumé : Disruptions to the maternally inherited allele UBE3A, encoding for an E3 ubiquitin ligase, leads to the manifestation of Angelman Syndrome (AS). While this disorder is rare, the symptoms are severe and lifelong including but not limited to: intractable seizures, abnormal EEG's, ataxic gait, lack of speech, and most notably an abnormally happy demeanor with easily provoked laughter. Currently, little is known about the neurophysiological underpinnings of UBE3A leading to such globally severe phenotypes. Utilizing the newest AS rat model, comprised of a full UBE3A deletion, we aimed to elucidate novel mechanistic actions and potential therapeutic targets. This report demonstrates for the first time that catalytically active UBE3A protein is detectable within cerebrospinal fluid (CSF) of wild type rats but distinctly absent in AS rat CSF. Microdialysis within the rat hippocampus also showed that UBE3A protein is located in the interstitial fluid of wild type rat brains but absent in AS animals. This protein maintains catalytic activity and appears to be regulated in a dynamic activity-dependent manner. LAY SUMMARY: Angelman syndrome (AS) is a rare genetic disorder caused by the loss of the UBE3A gene within the central nervous system. Although we have identified the gene responsible for AS, we still have a long way to go to fully understand its function in vivo. Here we report that UBE3A is present within normal cerebrospinal fluid (CSF) but distinctly absent in AS CSF. Furthermore, we demonstrate that UBE3A is secreted and that this may occur in a dynamic activity-dependent fashion. Extracellular UBE3A maintained its ubiquitinating activity, thus suggesting that UBE3A may have a novel role outside of neurons. Autism Res 2021, 14: 645-655. © 2021 International Society for Autism Research and Wiley Periodicals LLC. En ligne : http://dx.doi.org/10.1002/aur.2475 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=443

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