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Gayane Aghakhanyan, Paolo Bonanni, Giovanna Randazzo, Sara Nappi, Federica Tessarotto, Lara De Martin, Francesca Frijia, Daniele De Marchi, Francesco De Masi, Beate Kuppers, Francesco Lombardo, Davide Caramella, Domenico Montanaro
Angelman syndrome (AS) is a rare neurogenetic disorder due to loss of expression of maternal ubiquitin-protein ligase E3A (UBE3A) gene. It is characterized by severe developmental delay, speech impairment, movement or balance disorder and typical behavioral uniqueness. Affected individuals show normal magnetic resonance imaging (MRI) findings, although mild dysmyelination may be observed. In this study, we adopted a quantitative MRI analysis with voxel-based morphometry (FSL-VBM) method to investigate disease-related changes in the cortical/subcortical grey matter (GM) structures...
2016: PloS One
Karin Buiting, Charles Williams, Bernhard Horsthemke
Angelman syndrome is a rare neurogenetic disorder that is characterized by microcephaly, severe intellectual deficit, speech impairment, epilepsy, EEG abnormalities, ataxic movements, tongue protrusion, paroxysms of laughter, abnormal sleep patterns, and hyperactivity. Angelman syndrome results from loss of function of the imprinted UBE3A (ubiquitin-protein ligase E3A) gene on chromosome 15q11.2-q13. This loss of function can be caused by a mutation on the maternal allele, a 5-7 Mb deletion of the maternally inherited chromosomal region, paternal uniparental disomy of chromosome 15, or an imprinting defect...
October 2016: Nature Reviews. Neurology
Kevin A Hope, Mark S LeDoux, Lawrence T Reiter
In mammals, expression of UBE3A is epigenetically regulated in neurons and expression is restricted to the maternal copy of UBE3A. A recent report claimed that Drosophila melanogaster UBE3A homolog (Dube3a) is preferentially expressed from the maternal allele in fly brain, inferring an imprinting mechanism. However, complex epigenetic regulatory features of the mammalian imprinting center are not present in Drosophila, and allele specific expression of Dube3a has not been documented. We used behavioral and electrophysiological analysis of the Dube3a loss-of-function allele (Dube3a(15b)) to investigate Dube3a imprinting in fly neurons...
August 11, 2016: Epigenetics: Official Journal of the DNA Methylation Society
Imran Jamal, Vipendra Kumar, Naman Vatsa, Brijesh Kumar Singh, Shashi Shekhar, Ankit Sharma, Nihar Ranjan Jana
Angelman syndrome (AS) is a neurodevelopmental disorder largely caused by the loss of function of maternally inherited UBE3A. UBE3A-maternal deficient mice (AS mice) exhibit many typical features of AS including cognitive and motor deficits but the underlying mechanism of these behavioral abnormalities is poorly understood. Here, we demonstrate that rearing of AS mice in the enriched environment for prolonged period significantly improved their cognitive and motor dysfunction. Enriched environment also restored elevated serum corticosterone level and reduced anxiety-like behaviors in these mice...
September 1, 2016: Molecular Neurobiology
Mojgan Padash Barmchi, Mary Gilbert, Miranda Thomas, Lawrence Banks, Bing Zhang, Vanessa J Auld
Cervical cancer is one of the leading causes of cancer death in women worldwide. The causative agents of cervical cancers, high-risk human papillomaviruses (HPVs), cause cancer through the action of two oncoproteins, E6 and E7. The E6 oncoprotein cooperates with an E3 ubiquitin ligase (UBE3A) to target the p53 tumour suppressor and important polarity and junctional PDZ proteins for proteasomal degradation, activities that are believed to contribute towards malignancy. However, the causative link between degradation of PDZ proteins and E6-mediated malignancy is largely unknown...
August 2016: PLoS Pathogens
Dongmei Wang, Ellen S Mitchell
Brain glucose hypometabolism is a common feature of Alzheimer's disease (AD). Previous studies have shown that cognition is improved by providing AD patients with an alternate energy source: ketones derived from either ketogenic diet or supplementation with medium chain triglycerides (MCT). Recently, data on the neuroprotective capacity of MCT-derived medium chain fatty acids (MCFA) suggest 8-carbon and 10-carbon MCFA may have cognition-enhancing properties which are not related to ketone production. We investigated the effect of 8 week treatment with MCT8, MCT10 or sunflower oil supplementation (5% by weight of chow diet) in 21 month old Wistar rats...
2016: PloS One
Jana Stanurova, Anika Neureiter, Michaela Hiber, Hannah de Oliveira Kessler, Kristin Stolp, Roman Goetzke, Diana Klein, Agnes Bankfalvi, Hannes Klump, Laura Steenpass
Genomic imprinting is an epigenetic phenomenon resulting in parent-of-origin-specific gene expression that is regulated by a differentially methylated region. Gene mutations or failures in the imprinting process lead to the development of imprinting disorders, such as Angelman syndrome. The symptoms of Angelman syndrome are caused by the absence of functional UBE3A protein in neurons of the brain. To create a human neuronal model for Angelman syndrome, we reprogrammed dermal fibroblasts of a patient carrying a defined three-base pair deletion in UBE3A into induced pluripotent stem cells (iPSCs)...
2016: Scientific Reports
Alain C Burette, Matthew C Judson, Susan Burette, Kristen D Phend, Benjamin D Philpot, Richard J Weinberg
Ubiquitination regulates a broad array of cellular processes, and defective ubiquitination is implicated in several neurological disorders. Loss of the E3 ubiquitin-protein ligase UBE3A causes Angelman syndrome. Despite its clinical importance, the normal role of UBE3A in neurons is still unclear. As a step toward deciphering its possible functions, we performed high-resolution light and electron microscopic immunocytochemistry. We report a broad distribution of UBE3A in neurons, highlighted by concentrations in axon terminals and euchromatin-rich nuclear domains...
June 23, 2016: Journal of Comparative Neurology
Line Granild Bie Mertz, Rikke Christensen, Ida Vogel, Jens Michael Hertz, John R Østergaard
BACKGROUND: Angelman syndrome (AS) is a neurogenetic disorder characterized by intellectual disability, epilepsy, and low threshold for laughter. AIMS: We investigated the occurrence and severity of epilepsy and laughter-induced loss of postural muscle tone determined by the different genetic subtypes. METHODS: This study included 39 children with AS. Deletion breakpoints were determined by high resolution CGH microarray (1×1M Agilent). Clinical data were based on a parent interview and medical record review...
September 2016: Research in Developmental Disabilities
K Wang, Y T Li, M Hou
Angelman syndrome (AS) is a neurogenetic disorder caused by a defect in the expression of the maternally inherited ubiquitin protein ligase E3A (UBE3A) gene in chromosome 15. The most common genetic defects include maternal deletions in chromosome 15q11-13; however, paternal uniparental disomy and imprinting defects allow for the identification of mutations in UBE3A in 10% of patients with AS. The aim of this study was to validate the clinical features and genetic polymorphisms of AS, and to discuss the relationship between functional language lateralization and the arcuate fasciculus in the Broca's and Wernicke's areas...
2016: Genetics and Molecular Research: GMR
Kelly A Jones, Ji Eun Han, Jason P DeBruyne, Benjamin D Philpot
Mutations or deletions of the maternal allele of the UBE3A gene cause Angelman syndrome (AS), a severe neurodevelopmental disorder. The paternal UBE3A/Ube3a allele becomes epigenetically silenced in most neurons during postnatal development in humans and mice; hence, loss of the maternal allele largely eliminates neuronal expression of UBE3A protein. However, recent studies suggest that paternal Ube3a may escape silencing in certain neuron populations, allowing for persistent expression of paternal UBE3A protein...
2016: Scientific Reports
Wenhua Li, Aiyu Yao, Hui Zhi, Kuldeep Kaur, Yong-Chuan Zhu, Mingyue Jia, Hui Zhao, Qifu Wang, Shan Jin, Guoli Zhao, Zhi-Qi Xiong, Yong Q Zhang
Altered expression of the E3 ubiquitin ligase UBE3A, which is involved in protein degradation through the proteasome-mediated pathway, is associated with neurodevelopmental and behavioral defects observed in Angelman syndrome (AS) and autism. However, little is known about the neuronal function of UBE3A and the pathogenesis of UBE3A-associated disorders. To understand the in vivo function of UBE3A in the nervous system, we generated multiple mutations of ube3a, the Drosophila ortholog of UBE3A. We found a significantly increased number of total boutons and satellite boutons in conjunction with compromised endocytosis in the neuromuscular junctions (NMJs) of ube3a mutants compared to the wild type...
May 2016: PLoS Genetics
Angela M Mabb, Jeremy M Simon, Ian F King, Hyeong-Min Lee, Lin-Kun An, Benjamin D Philpot, Mark J Zylka
Topoisomerase 1 (TOP1) inhibitors, including camptothecin and topotecan, covalently trap TOP1 on DNA, creating cleavage complexes (cc's) that must be resolved before gene transcription and DNA replication can proceed. We previously found that topotecan reduces the expression of long (>100 kb) genes and unsilences the paternal allele of Ube3a in neurons. Here, we sought to evaluate overlap between TOP1cc-dependent and -independent gene regulation in neurons. To do this, we utilized Top1 conditional knockout mice, Top1 knockdown, the CRISPR-Cas9 system to delete Top1, TOP1 catalytic inhibitors that do not generate TOP1cc's, and a TOP1 mutation (T718A) that stabilizes TOP1cc's...
2016: PloS One
H M Luk, Ivan F M Lo
AS(OMIM #105830) is a neurodevelopmental disease that characterized by severe intellectual disability, lack of speech, happy disposition, ataxia, epilepsy and distinct behavioural profile. A tertiary wide study was performed in Hong Kong with aim to examine the clinical and molecular features, genotype-phenotype correlation of the Angelman syndrome (AS) patients. There were total 55 molecularly confirmed AS between January 1995 to September 2015 for review. 65.5% of them were caused by maternal microdeletion, 10...
May 9, 2016: European Journal of Medical Genetics
Jiandong Sun, Yan Liu, Jennifer Tran, Patrick O'Neal, Michel Baudry, Xiaoning Bi
Emerging evidence is implicating abnormal activation of the mechanistic target of rapamycin (mTOR) pathway in several monogenetic neuropsychiatric disorders, including Angelman syndrome (AS), which is caused by deficiency in maternally inherited UBE3A. Using an AS mouse model, we show that semi-chronic rapamycin treatment improves long-term potentiation (LTP) and actin polymerization in hippocampal slices, spine morphology, and fear-conditioning learning. Activity of mTORC1 and of its downstream substrate, S6K1, was increased in hippocampus of AS mice...
May 12, 2016: Cellular and Molecular Life Sciences: CMLS
Pin-Fang Chen, Jack S Hsiao, Carissa L Sirois, Stormy J Chamberlain
Angelman Syndrome (AS) is a rare neurodevelopmental disorder caused by loss of function of the maternally inherited copy of UBE3A, an imprinted gene expressed biallelically in most tissues, but expressed exclusively from the maternal allele in neurons. Active transcription of the neuron-specific long non-coding RNA (lncRNA), UBE3A-ATS, has been shown to silence paternal UBE3A. We hypothesized that alternative splicing factors RBFOX2 and RBFOX1 might mediate splicing changes and result in the transcription of UBE3A-ATS in neurons...
2016: Scientific Reports
Hyojin Kim, Portia A Kunz, Richard Mooney, Benjamin D Philpot, Spencer L Smith
UNLABELLED: Dendritic spines are a morphological feature of the majority of excitatory synapses in the mammalian neocortex and are motile structures with shapes and lifetimes that change throughout development. Proper cortical development and function, including cortical contributions to learning and memory formation, require appropriate experience-dependent dendritic spine remodeling. Dendritic spine abnormalities have been reported for many neurodevelopmental disorders, including Angelman syndrome (AS), which is caused by the loss of the maternally inherited UBE3A allele (encoding ubiquitin protein ligase E3A)...
April 27, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Masamitsu Eitoku, Narufumi Suganuma, Hidenori Kiyosawa
In vitro differentiation systems of mouse embryonic stem cells (ESCs) are widely used as tools for studies of cell differentiation, organogenesis, and regenerative medicine. We have studied the regulation of neuron-specific imprinting genes, Ube3a and its antisense transcripts (Ube3a ATS), using in vitro neuronal differentiation of F1 hybrid ESCs. Each different non-adherent plate used for embryoid body (EB) formation during differentiation is associated with different costs; notably, plates coated with 2-methacryloyloxyethyl phosphorylcholine (MPC) polymer are more expensive than untreated polystyrene plates...
April 8, 2016: Cytotechnology
Emanuela Santini, Eric Klann
Epilepsy in Angelman Syndrome is thought to originate from an imbalance between local excitatory-inhibitory circuits that results in a generalized hyperexcitability. In this issue of Neuron, Judson et al. (2016) demonstrate that selective maternal deletion of Ube3a in cortical GABAergic neurons causes circuit hyperexcitability, increased seizure severity, and EEG abnormalities.
April 6, 2016: Neuron
Matthew C Judson, Michael L Wallace, Michael S Sidorov, Alain C Burette, Bin Gu, Geeske M van Woerden, Ian F King, Ji Eun Han, Mark J Zylka, Ype Elgersma, Richard J Weinberg, Benjamin D Philpot
Loss of maternal UBE3A causes Angelman syndrome (AS), a neurodevelopmental disorder associated with severe epilepsy. We previously implicated GABAergic deficits onto layer (L) 2/3 pyramidal neurons in the pathogenesis of neocortical hyperexcitability, and perhaps epilepsy, in AS model mice. Here we investigate consequences of selective Ube3a loss from either GABAergic or glutamatergic neurons, focusing on the development of hyperexcitability within L2/3 neocortex and in broader circuit and behavioral contexts...
April 6, 2016: Neuron
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