Assessing the requirements of prenatal UBE3A expression for rescue of behavioral phenotypes in a mouse model for Angelman syndrome / Monica SONZOGNI in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 70 p. Titre : Assessing the requirements of prenatal UBE3A expression for rescue of behavioral phenotypes in a mouse model for Angelman syndrome Type de document : texte imprimé Auteurs : Monica SONZOGNI, Auteur ; Peipei ZHAI, Auteur ; Edwin J. MIENTJES, Auteur ; Geeske M. VAN WOERDEN, Auteur ; Ype ELGERSMA, Auteur Article en page(s) : 70 p. Langues : Anglais (eng) Mots-clés : ASO therapy  Angelman syndrome  Behavior  Critical period  Mouse model  Ube3a Index. décimale : PER Périodiques Résumé : BACKGROUND: Angelman syndrome (AS) is a rare neurodevelopmental disorder caused by the loss of functional ubiquitin protein ligase E3A (UBE3A). In neurons, UBE3A expression is tightly regulated by a mechanism of imprinting which suppresses the expression of the paternal UBE3A allele. Promising treatment strategies for AS are directed at activating paternal UBE3A gene expression. However, for such strategies to be successful, it is important to know when such a treatment should start, and how much UBE3A expression is needed for normal embryonic brain development. METHODS: Using a conditional mouse model of AS, we further delineated the critical period for UBE3A expression during early brain development. Ube3a gene expression was induced around the second week of gestation and mouse phenotypes were assessed using a behavioral test battery. To investigate the requirements of embryonic UBE3A expression, we made use of mice in which the paternal Ube3a allele was deleted. RESULTS: We observed a full behavioral rescue of the AS mouse model phenotypes when Ube3a gene reactivation was induced around the start of the last week of mouse embryonic development. We found that full silencing of the paternal Ube3a allele was not completed till the first week after birth but that deletion of the paternal Ube3a allele had no significant effect on the assessed phenotypes. LIMITATIONS: Direct translation to human is limited, as we do not precisely know how human and mouse brain development aligns over gestational time. Moreover, many of the assessed phenotypes have limited translational value, as the underlying brain regions involved in these tasks are largely unknown. CONCLUSIONS: Our findings provide further important insights in the requirement of UBE3A expression during brain development. We found that loss of up to 50% of UBE3A protein during prenatal mouse brain development does not significantly impact the assessed mouse behavioral phenotypes. Together with previous findings, our results indicate that the most critical function for mouse UBE3A lies in the early postnatal period between birth and P21. En ligne : http://dx.doi.org/10.1186/s13229-020-00376-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=433 [article] Assessing the requirements of prenatal UBE3A expression for rescue of behavioral phenotypes in a mouse model for Angelman syndrome [texte imprimé] / Monica SONZOGNI, Auteur ; Peipei ZHAI, Auteur ; Edwin J. MIENTJES, Auteur ; Geeske M. VAN WOERDEN, Auteur ; Ype ELGERSMA, Auteur . - 70 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 70 p. Mots-clés : ASO therapy  Angelman syndrome  Behavior  Critical period  Mouse model  Ube3a Index. décimale : PER Périodiques Résumé : BACKGROUND: Angelman syndrome (AS) is a rare neurodevelopmental disorder caused by the loss of functional ubiquitin protein ligase E3A (UBE3A). In neurons, UBE3A expression is tightly regulated by a mechanism of imprinting which suppresses the expression of the paternal UBE3A allele. Promising treatment strategies for AS are directed at activating paternal UBE3A gene expression. However, for such strategies to be successful, it is important to know when such a treatment should start, and how much UBE3A expression is needed for normal embryonic brain development. METHODS: Using a conditional mouse model of AS, we further delineated the critical period for UBE3A expression during early brain development. Ube3a gene expression was induced around the second week of gestation and mouse phenotypes were assessed using a behavioral test battery. To investigate the requirements of embryonic UBE3A expression, we made use of mice in which the paternal Ube3a allele was deleted. RESULTS: We observed a full behavioral rescue of the AS mouse model phenotypes when Ube3a gene reactivation was induced around the start of the last week of mouse embryonic development. We found that full silencing of the paternal Ube3a allele was not completed till the first week after birth but that deletion of the paternal Ube3a allele had no significant effect on the assessed phenotypes. LIMITATIONS: Direct translation to human is limited, as we do not precisely know how human and mouse brain development aligns over gestational time. Moreover, many of the assessed phenotypes have limited translational value, as the underlying brain regions involved in these tasks are largely unknown. CONCLUSIONS: Our findings provide further important insights in the requirement of UBE3A expression during brain development. We found that loss of up to 50% of UBE3A protein during prenatal mouse brain development does not significantly impact the assessed mouse behavioral phenotypes. Together with previous findings, our results indicate that the most critical function for mouse UBE3A lies in the early postnatal period between birth and P21. En ligne : http://dx.doi.org/10.1186/s13229-020-00376-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=433

The role of ubiquitin ligase E3A in polarized contact guidance and rescue strategies in UBE3A-deficient hippocampal neurons / Ilaria TONAZZINI in Molecular Autism, 10 (2019)  

Public ISBD [article]  inMolecular Autism > 10 (2019) . - 41 p. Titre : The role of ubiquitin ligase E3A in polarized contact guidance and rescue strategies in UBE3A-deficient hippocampal neurons Type de document : texte imprimé Auteurs : Ilaria TONAZZINI, Auteur ; Geeske M. VAN WOERDEN, Auteur ; Cecilia MASCIULLO, Auteur ; Edwin J. MIENTJES, Auteur ; Ype ELGERSMA, Auteur ; Marco CECCHINI, Auteur Article en page(s) : 41 p. Langues : Anglais (eng) Mots-clés : 15q duplication autism  Angelman syndrome  Axonal guidance  Contact guidance  Cytoskeleton  Microgratings  Nocodazole  Ubiquitin ligase E3a (UBE3A) Index. décimale : PER Périodiques Résumé : Background: Although neuronal extracellular sensing is emerging as crucial for brain wiring and therefore plasticity, little is known about these processes in neurodevelopmental disorders. Ubiquitin protein ligase E3A (UBE3A) plays a key role in neurodevelopment. Lack of UBE3A leads to Angelman syndrome (AS), while its increase is among the most prevalent genetic causes of autism (e.g., Dup15q syndrome). By using microstructured substrates that can induce specific directional stimuli in cells, we previously found deficient topographical contact guidance in AS neurons, which was linked to a dysregulated activation of the focal adhesion pathway. Methods: Here, we study axon and dendrite contact guidance and neuronal morphological features of wild-type, AS, and UBE3A-overexpressing neurons (Dup15q autism model) on micrograting substrates, with the aim to clarify the role of UBE3A in neuronal guidance. Results: We found that loss of axonal contact guidance is specific for AS neurons while UBE3A overexpression does not affect neuronal directional polarization along microgratings. Deficits at the level of axonal branching, growth cone orientation and actin fiber content, focal adhesion (FA) effectors, and actin fiber-binding proteins were observed in AS neurons. We tested different rescue strategies for restoring correct topographical guidance in AS neurons on microgratings, by either UBE3A protein re-expression or by pharmacological treatments acting on cytoskeleton contractility. Nocodazole, a drug that depolymerizes microtubules and increases cell contractility, rescued AS axonal alignment to the gratings by partially restoring focal adhesion pathway activation. Surprisingly, UBE3A re-expression only resulted in partial rescue of the phenotype. Conclusions: We identified a specific in vitro deficit in axonal topographical guidance due selectively to the loss of UBE3A, and we further demonstrate that this defective guidance can be rescued to a certain extent by pharmacological or genetic treatment strategies. Overall, cytoskeleton dynamics emerge as important partners in UBE3A-mediated contact guidance responses. These results support the view that UBE3A-related deficits in early neuronal morphogenesis may lead to defective neuronal connectivity and plasticity. En ligne : http://dx.doi.org/10.1186/s13229-019-0293-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=414 [article] The role of ubiquitin ligase E3A in polarized contact guidance and rescue strategies in UBE3A-deficient hippocampal neurons [texte imprimé] / Ilaria TONAZZINI, Auteur ; Geeske M. VAN WOERDEN, Auteur ; Cecilia MASCIULLO, Auteur ; Edwin J. MIENTJES, Auteur ; Ype ELGERSMA, Auteur ; Marco CECCHINI, Auteur . - 41 p. Langues : Anglais (eng) in Molecular Autism > 10 (2019) . - 41 p. Mots-clés : 15q duplication autism  Angelman syndrome  Axonal guidance  Contact guidance  Cytoskeleton  Microgratings  Nocodazole  Ubiquitin ligase E3a (UBE3A) Index. décimale : PER Périodiques Résumé : Background: Although neuronal extracellular sensing is emerging as crucial for brain wiring and therefore plasticity, little is known about these processes in neurodevelopmental disorders. Ubiquitin protein ligase E3A (UBE3A) plays a key role in neurodevelopment. Lack of UBE3A leads to Angelman syndrome (AS), while its increase is among the most prevalent genetic causes of autism (e.g., Dup15q syndrome). By using microstructured substrates that can induce specific directional stimuli in cells, we previously found deficient topographical contact guidance in AS neurons, which was linked to a dysregulated activation of the focal adhesion pathway. Methods: Here, we study axon and dendrite contact guidance and neuronal morphological features of wild-type, AS, and UBE3A-overexpressing neurons (Dup15q autism model) on micrograting substrates, with the aim to clarify the role of UBE3A in neuronal guidance. Results: We found that loss of axonal contact guidance is specific for AS neurons while UBE3A overexpression does not affect neuronal directional polarization along microgratings. Deficits at the level of axonal branching, growth cone orientation and actin fiber content, focal adhesion (FA) effectors, and actin fiber-binding proteins were observed in AS neurons. We tested different rescue strategies for restoring correct topographical guidance in AS neurons on microgratings, by either UBE3A protein re-expression or by pharmacological treatments acting on cytoskeleton contractility. Nocodazole, a drug that depolymerizes microtubules and increases cell contractility, rescued AS axonal alignment to the gratings by partially restoring focal adhesion pathway activation. Surprisingly, UBE3A re-expression only resulted in partial rescue of the phenotype. Conclusions: We identified a specific in vitro deficit in axonal topographical guidance due selectively to the loss of UBE3A, and we further demonstrate that this defective guidance can be rescued to a certain extent by pharmacological or genetic treatment strategies. Overall, cytoskeleton dynamics emerge as important partners in UBE3A-mediated contact guidance responses. These results support the view that UBE3A-related deficits in early neuronal morphogenesis may lead to defective neuronal connectivity and plasticity. En ligne : http://dx.doi.org/10.1186/s13229-019-0293-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=414

UBE3A reinstatement restores behaviorand proteome in an Angelman syndrome mouse model of imprinting defects / Claudia MILAZZO in Molecular Autism, 16 (2025)  

Public ISBD [article]  inMolecular Autism > 16 (2025) . - 45 Titre : UBE3A reinstatement restores behaviorand proteome in an Angelman syndrome mouse model of imprinting defects Type de document : texte imprimé Auteurs : Claudia MILAZZO, Auteur ; Ramanathan NARAYANAN, Auteur ; Solveig BADILLO, Auteur ; Silvia WANG, Auteur ; Rosaisela ALMAND, Auteur ; Roos MONSHOUWER, Auteur ; Manuel TZOUROS, Auteur ; Sabrina GOLLING, Auteur ; Edwin J. MIENTJES, Auteur ; Stormy J. CHAMBERLAIN, Auteur ; Thomas KREMER, Auteur ; Ype ELGERSMA, Auteur ; Claudia MILAZZO, Auteur ; Ramanathan NARAYANAN, Auteur ; Solveig BADILLO, Auteur ; Silvia WANG, Auteur ; Rosaisela ALMAND, Auteur ; Roos MONSHOUWER, Auteur ; Manuel TZOUROS, Auteur ; Sabrina GOLLING, Auteur ; Edwin J. MIENTJES, Auteur ; Stormy J. CHAMBERLAIN, Auteur ; Thomas KREMER, Auteur ; Ype ELGERSMA, Auteur Article en page(s) : 45 Langues : Anglais (eng) Mots-clés : Animals  Angelman Syndrome/genetics/metabolism  Ubiquitin-Protein Ligases/genetics/metabolism  Genomic Imprinting  Disease Models, Animal  Mice  Proteome/metabolism  Behavior, Animal  Male  Female  Oligonucleotides, Antisense  Angelman syndrome  Antisense oligonucleotide  Behavior  Imprinting defects  Mouse model  Proteome  were conducted in accordance with the European Commission Council Directive  2010/63/EU (CCD license AVD101002016791 and AVD10100202216352). Consent for  publication: All authors have approved the final manuscript and consent for  publication. Competing interests: The authors declare no competing interests. Index. décimale : PER Périodiques Résumé : BACKGROUND: Angelman Syndrome (AS) is a severe neurodevelopmental disorder with only symptomatic treatment currently available. The primary cause of AS is loss of functional UBE3A protein. This can be caused by deletions in the maternal 15q11-q13 region, maternal AS-imprinting center defects (mICD), paternal uniparental disomy of chromosome 15 (UPD) or mutations within the UBE3A gene. Current mouse models are Ube3a-centric and do not address expression changes of other genes in the 15q11-q13 locus on the pathophysiology of AS. This limits the ability to discern differences in therapeutic responses to current UBE3A-targeting strategies and hampers the identification of novel therapeutics/co-therapeutics. METHODS: Using a mouse line that harbors a maternally inherited mutation affecting the AS-PWS imprinting center ('mICD mice'), we studied the impact of the mICD or UPD AS subtype on behavior, seizure susceptibility and proteome. Additionally, by using mice overexpressing two copies of Ube3a or antisense oligonucleotide (ASO) targeting Ube3a-ATS, we analyzed the impact of bi-allelic Ube3a activation on behavior and proteome. RESULTS: mICD mice showed 80% reduction in UBE3A protein, bi-allelic expression of Ube3a-ATS and Mkrn3-Snord115 gene cluster, leading to robust AS behavioral deficits and proteome alterations similar to Ube3a(m-/p+) mice. Genetic UBE3A overexpression in mICD mice, mimicking therapeutic strategies that effectively activate the biallelic silenced Ube3a gene, resulted in a complete rescue of all behavioral phenotypes, seizure susceptibility and proteome alterations. Subsequently, treatment with an antisense oligonucleotide (ASO) to directly activate the biallelic silenced Ube3a gene in mICD mice also resulted in efficient reinstatement of UBE3A, 30% higher relative to WT, alongside a partial rescue of behavioral phenotypes. LIMITATIONS: Despite using a highly robust AS-specific behavioral battery, we did not investigate readouts such as neuronal activity and sleep, for which impairments in Ube3a(m-/p+) mice were described. CONCLUSIONS: Taken together, these findings demonstrate that the loss of UBE3A protein is the primary factor underlying AS phenotypes in this mICD/UPD mouse model of AS, while the biallelic expressed genes in this locus play either a marginal or yet unidentified role. These findings also corroborate UBE3A reinstatement as an attractive therapeutic strategy for AS individuals carrying an mICD or UPD mutation. En ligne : https://dx.doi.org/10.1186/s13229-025-00675-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=569 [article] UBE3A reinstatement restores behaviorand proteome in an Angelman syndrome mouse model of imprinting defects [texte imprimé] / Claudia MILAZZO, Auteur ; Ramanathan NARAYANAN, Auteur ; Solveig BADILLO, Auteur ; Silvia WANG, Auteur ; Rosaisela ALMAND, Auteur ; Roos MONSHOUWER, Auteur ; Manuel TZOUROS, Auteur ; Sabrina GOLLING, Auteur ; Edwin J. MIENTJES, Auteur ; Stormy J. CHAMBERLAIN, Auteur ; Thomas KREMER, Auteur ; Ype ELGERSMA, Auteur ; Claudia MILAZZO, Auteur ; Ramanathan NARAYANAN, Auteur ; Solveig BADILLO, Auteur ; Silvia WANG, Auteur ; Rosaisela ALMAND, Auteur ; Roos MONSHOUWER, Auteur ; Manuel TZOUROS, Auteur ; Sabrina GOLLING, Auteur ; Edwin J. MIENTJES, Auteur ; Stormy J. CHAMBERLAIN, Auteur ; Thomas KREMER, Auteur ; Ype ELGERSMA, Auteur . - 45. Langues : Anglais (eng) in Molecular Autism > 16 (2025) . - 45 Mots-clés : Animals  Angelman Syndrome/genetics/metabolism  Ubiquitin-Protein Ligases/genetics/metabolism  Genomic Imprinting  Disease Models, Animal  Mice  Proteome/metabolism  Behavior, Animal  Male  Female  Oligonucleotides, Antisense  Angelman syndrome  Antisense oligonucleotide  Behavior  Imprinting defects  Mouse model  Proteome  were conducted in accordance with the European Commission Council Directive  2010/63/EU (CCD license AVD101002016791 and AVD10100202216352). Consent for  publication: All authors have approved the final manuscript and consent for  publication. Competing interests: The authors declare no competing interests. Index. décimale : PER Périodiques Résumé : BACKGROUND: Angelman Syndrome (AS) is a severe neurodevelopmental disorder with only symptomatic treatment currently available. The primary cause of AS is loss of functional UBE3A protein. This can be caused by deletions in the maternal 15q11-q13 region, maternal AS-imprinting center defects (mICD), paternal uniparental disomy of chromosome 15 (UPD) or mutations within the UBE3A gene. Current mouse models are Ube3a-centric and do not address expression changes of other genes in the 15q11-q13 locus on the pathophysiology of AS. This limits the ability to discern differences in therapeutic responses to current UBE3A-targeting strategies and hampers the identification of novel therapeutics/co-therapeutics. METHODS: Using a mouse line that harbors a maternally inherited mutation affecting the AS-PWS imprinting center ('mICD mice'), we studied the impact of the mICD or UPD AS subtype on behavior, seizure susceptibility and proteome. Additionally, by using mice overexpressing two copies of Ube3a or antisense oligonucleotide (ASO) targeting Ube3a-ATS, we analyzed the impact of bi-allelic Ube3a activation on behavior and proteome. RESULTS: mICD mice showed 80% reduction in UBE3A protein, bi-allelic expression of Ube3a-ATS and Mkrn3-Snord115 gene cluster, leading to robust AS behavioral deficits and proteome alterations similar to Ube3a(m-/p+) mice. Genetic UBE3A overexpression in mICD mice, mimicking therapeutic strategies that effectively activate the biallelic silenced Ube3a gene, resulted in a complete rescue of all behavioral phenotypes, seizure susceptibility and proteome alterations. Subsequently, treatment with an antisense oligonucleotide (ASO) to directly activate the biallelic silenced Ube3a gene in mICD mice also resulted in efficient reinstatement of UBE3A, 30% higher relative to WT, alongside a partial rescue of behavioral phenotypes. LIMITATIONS: Despite using a highly robust AS-specific behavioral battery, we did not investigate readouts such as neuronal activity and sleep, for which impairments in Ube3a(m-/p+) mice were described. CONCLUSIONS: Taken together, these findings demonstrate that the loss of UBE3A protein is the primary factor underlying AS phenotypes in this mICD/UPD mouse model of AS, while the biallelic expressed genes in this locus play either a marginal or yet unidentified role. These findings also corroborate UBE3A reinstatement as an attractive therapeutic strategy for AS individuals carrying an mICD or UPD mutation. En ligne : https://dx.doi.org/10.1186/s13229-025-00675-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=569

---

1 (1 - 3 / 3) Par page : 25 50 100 200