Delayed loss of UBE3A reduces the expression of Angelman syndrome-associated phenotypes / M. SONZOGNI in Molecular Autism, 10 (2019)  

Public ISBD [article]  inMolecular Autism > 10 (2019) . - 23p. Titre : Delayed loss of UBE3A reduces the expression of Angelman syndrome-associated phenotypes Type de document : Texte imprimé et/ou numérique Auteurs : M. SONZOGNI, Auteur ; J. HAKONEN, Auteur ; M. BERNABE KLEIJN, Auteur ; S. SILVA-SANTOS, Auteur ; M. C. JUDSON, Auteur ; B. D. PHILPOT, Auteur ; G. M. VAN WOERDEN, Auteur ; Y. ELGERSMA, Auteur Article en page(s) : 23p. Langues : Anglais (eng) Mots-clés : Angelman syndrome  Autism spectrum disorder  Mouse model  Phenotype  Seizure  Ube3a Index. décimale : PER Périodiques Résumé : Background: Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by mutations affecting UBE3A gene expression. Previous studies in mice revealed distinct critical periods during neurodevelopment in which reactivation of Ube3a gene expression can prevent the onset of behavioral deficits. Whether UBE3A is required for brain function throughout life is unknown. Here, we address the importance of maintaining UBE3A expression after normal brain development. Findings: Using a conditional mouse, we deleted the Ube3a gene at three ages spanning brain maturation. We assessed the consequences of Ube3a gene deletion by testing the mice in behavioral tasks previously shown to produce robust phenotypes in AS model mice. Early embryonic deletion of Ube3a recapitulated all behavioral deficits of AS mice. In contrast, Ube3a gene deletion at 3 or 12 weeks of age did not have a significant effect on most behavioral tasks and did not increase seizure sensitivity. Conclusions: Taken together, these results emphasize that UBE3A critically impacts early brain development, but plays a more limited role in adulthood. Our findings provide important considerations for upcoming clinical trials in which UBE3A gene expression is reactivated and suggest that even transient UBE3A reinstatement during a critical window of early development is likely to prevent most adverse Angelman syndrome phenotypes. However, sustained UBE3A expression into adulthood is probably needed for optimal clinical benefit. En ligne : http://dx.doi.org/10.1186/s13229-019-0277-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=402 [article] Delayed loss of UBE3A reduces the expression of Angelman syndrome-associated phenotypes [Texte imprimé et/ou numérique] / M. SONZOGNI, Auteur ; J. HAKONEN, Auteur ; M. BERNABE KLEIJN, Auteur ; S. SILVA-SANTOS, Auteur ; M. C. JUDSON, Auteur ; B. D. PHILPOT, Auteur ; G. M. VAN WOERDEN, Auteur ; Y. ELGERSMA, Auteur . - 23p. Langues : Anglais (eng) in Molecular Autism > 10 (2019) . - 23p. Mots-clés : Angelman syndrome  Autism spectrum disorder  Mouse model  Phenotype  Seizure  Ube3a Index. décimale : PER Périodiques Résumé : Background: Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by mutations affecting UBE3A gene expression. Previous studies in mice revealed distinct critical periods during neurodevelopment in which reactivation of Ube3a gene expression can prevent the onset of behavioral deficits. Whether UBE3A is required for brain function throughout life is unknown. Here, we address the importance of maintaining UBE3A expression after normal brain development. Findings: Using a conditional mouse, we deleted the Ube3a gene at three ages spanning brain maturation. We assessed the consequences of Ube3a gene deletion by testing the mice in behavioral tasks previously shown to produce robust phenotypes in AS model mice. Early embryonic deletion of Ube3a recapitulated all behavioral deficits of AS mice. In contrast, Ube3a gene deletion at 3 or 12 weeks of age did not have a significant effect on most behavioral tasks and did not increase seizure sensitivity. Conclusions: Taken together, these results emphasize that UBE3A critically impacts early brain development, but plays a more limited role in adulthood. Our findings provide important considerations for upcoming clinical trials in which UBE3A gene expression is reactivated and suggest that even transient UBE3A reinstatement during a critical window of early development is likely to prevent most adverse Angelman syndrome phenotypes. However, sustained UBE3A expression into adulthood is probably needed for optimal clinical benefit. En ligne : http://dx.doi.org/10.1186/s13229-019-0277-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=402

A new synaptic player leading to autism risk: Met receptor tyrosine kinase / M. C. JUDSON in Journal of Neurodevelopmental Disorders, 3-3 (September 2011)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 3-3 (September 2011) . - p.282-92 Titre : A new synaptic player leading to autism risk: Met receptor tyrosine kinase Type de document : Texte imprimé et/ou numérique Auteurs : M. C. JUDSON, Auteur ; K. L. EAGLESON, Auteur ; P. LEVITT, Auteur Article en page(s) : p.282-92 Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : The validity for assigning disorder risk to an autism spectrum disorder (ASD) candidate gene comes from convergent genetic, clinical, and developmental neurobiology data. Here, we review these lines of evidence from multiple human genetic studies, and non-human primate and mouse experiments that support the conclusion that the MET receptor tyrosine kinase (RTK) functions to influence synapse development in circuits relevant to certain core behavioral domains of ASD. There is association of both common functional alleles and rare copy number variants that impact levels of MET expression in the human cortex. The timing of Met expression is linked to axon terminal outgrowth and synaptogenesis in the developing rodent and primate forebrain, and both in vitro and in vivo studies implicate this RTK in dendritic branching, spine maturation, and excitatory connectivity in the neocortex. This impact can occur in a cell-nonautonomous fashion, emphasizing the unique role that Met plays in specific circuits relevant to ASD. En ligne : http://dx.doi.org/10.1007/s11689-011-9081-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=343 [article] A new synaptic player leading to autism risk: Met receptor tyrosine kinase [Texte imprimé et/ou numérique] / M. C. JUDSON, Auteur ; K. L. EAGLESON, Auteur ; P. LEVITT, Auteur . - p.282-92. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 3-3 (September 2011) . - p.282-92 Index. décimale : PER Périodiques Résumé : The validity for assigning disorder risk to an autism spectrum disorder (ASD) candidate gene comes from convergent genetic, clinical, and developmental neurobiology data. Here, we review these lines of evidence from multiple human genetic studies, and non-human primate and mouse experiments that support the conclusion that the MET receptor tyrosine kinase (RTK) functions to influence synapse development in circuits relevant to certain core behavioral domains of ASD. There is association of both common functional alleles and rare copy number variants that impact levels of MET expression in the human cortex. The timing of Met expression is linked to axon terminal outgrowth and synaptogenesis in the developing rodent and primate forebrain, and both in vitro and in vivo studies implicate this RTK in dendritic branching, spine maturation, and excitatory connectivity in the neocortex. This impact can occur in a cell-nonautonomous fashion, emphasizing the unique role that Met plays in specific circuits relevant to ASD. En ligne : http://dx.doi.org/10.1007/s11689-011-9081-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=343

Subcellular organization of UBE3A in human cerebral cortex / A. C. BURETTE in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 54p. Titre : Subcellular organization of UBE3A in human cerebral cortex Type de document : Texte imprimé et/ou numérique Auteurs : A. C. BURETTE, Auteur ; M. C. JUDSON, Auteur ; A. N. LI, Auteur ; E. F. CHANG, Auteur ; W. W. SEELEY, Auteur ; B. D. PHILPOT, Auteur ; R. J. WEINBERG, Auteur Article en page(s) : 54p. Langues : Anglais (eng) Mots-clés : Angelman syndrome  Axon terminal  e6-ap  Euchromatin  Mitochondria  UCSF Committee on Human Research and the University of Maryland Institutional  Review Board.All authors read and approved the final manuscript.The authors  declare that they have no competing interests.Springer Nature remains neutral  with regard to jurisdictional claims in published maps and institutional  affiliations. Index. décimale : PER Périodiques Résumé : Background: Loss of UBE3A causes Angelman syndrome, whereas excess UBE3A activity appears to increase the risk for autism. Despite this powerful association with neurodevelopmental disorders, there is still much to be learned about UBE3A, including its cellular and subcellular organization in the human brain. The issue is important, since UBE3A's localization is integral to its function. Methods: We used light and electron microscopic immunohistochemistry to study the cellular and subcellular distribution of UBE3A in the adult human cerebral cortex. Experiments were performed on multiple tissue sources, but our results focused on optimally preserved material, using surgically resected human temporal cortex of high ultrastructural quality from nine individuals. Results: We demonstrate that UBE3A is expressed in both glutamatergic and GABAergic neurons, and to a lesser extent in glial cells. We find that UBE3A in neurons has a non-uniform subcellular distribution. In somata, UBE3A preferentially concentrates in euchromatin-rich domains within the nucleus. Electron microscopy reveals that labeling concentrates in the head and neck of dendritic spines and is excluded from the PSD. Strongest labeling within the neuropil was found in axon terminals. Conclusions: By highlighting the subcellular compartments in which UBE3A is likely to function in the human neocortex, our data provide insight into the diverse functional capacities of this E3 ligase. These anatomical data may help to elucidate the role of UBE3A in Angelman syndrome and autism spectrum disorder. En ligne : https://dx.doi.org/10.1186/s13229-018-0238-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371 [article] Subcellular organization of UBE3A in human cerebral cortex [Texte imprimé et/ou numérique] / A. C. BURETTE, Auteur ; M. C. JUDSON, Auteur ; A. N. LI, Auteur ; E. F. CHANG, Auteur ; W. W. SEELEY, Auteur ; B. D. PHILPOT, Auteur ; R. J. WEINBERG, Auteur . - 54p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 54p. Mots-clés : Angelman syndrome  Axon terminal  e6-ap  Euchromatin  Mitochondria  UCSF Committee on Human Research and the University of Maryland Institutional  Review Board.All authors read and approved the final manuscript.The authors  declare that they have no competing interests.Springer Nature remains neutral  with regard to jurisdictional claims in published maps and institutional  affiliations. Index. décimale : PER Périodiques Résumé : Background: Loss of UBE3A causes Angelman syndrome, whereas excess UBE3A activity appears to increase the risk for autism. Despite this powerful association with neurodevelopmental disorders, there is still much to be learned about UBE3A, including its cellular and subcellular organization in the human brain. The issue is important, since UBE3A's localization is integral to its function. Methods: We used light and electron microscopic immunohistochemistry to study the cellular and subcellular distribution of UBE3A in the adult human cerebral cortex. Experiments were performed on multiple tissue sources, but our results focused on optimally preserved material, using surgically resected human temporal cortex of high ultrastructural quality from nine individuals. Results: We demonstrate that UBE3A is expressed in both glutamatergic and GABAergic neurons, and to a lesser extent in glial cells. We find that UBE3A in neurons has a non-uniform subcellular distribution. In somata, UBE3A preferentially concentrates in euchromatin-rich domains within the nucleus. Electron microscopy reveals that labeling concentrates in the head and neck of dendritic spines and is excluded from the PSD. Strongest labeling within the neuropil was found in axon terminals. Conclusions: By highlighting the subcellular compartments in which UBE3A is likely to function in the human neocortex, our data provide insight into the diverse functional capacities of this E3 ligase. These anatomical data may help to elucidate the role of UBE3A in Angelman syndrome and autism spectrum disorder. En ligne : https://dx.doi.org/10.1186/s13229-018-0238-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371

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