Abstract
Angelman syndrome (AS) is a severe disorder of postnatal brain development caused by neuron-specific loss of the HECT (homologous to E6AP carboxy terminus) domain E3 ubiquitin ligase Ube3a/E6AP. The cellular role of Ube3a remains enigmatic despite recent descriptions of synaptic and behavioral deficits in AS mouse models. Although neuron-specific imprinting is thought to limit the disease to the brain, Ube3a is expressed ubiquitously, suggesting a broader role in cellular function. In the current study, we demonstrate a profound structural disruption and cisternal swelling of the Golgi apparatus (GA) in the cortex of AS (UBE3A(m-/p+)) mice. In Ube3a knockdown cell lines and UBE3A(m-/p+) cortical neurons, the GA is severely under-acidified, leading to osmotic swelling. Both in vitro and in vivo, the loss of Ube3a and corresponding elevated pH of the GA is associated with a marked reduction in protein sialylation, a process highly dependent on intralumenal Golgi pH. Altered ion homeostasis of the GA may provide a common cellular pathophysiology underlying the diverse plasticity and neurodevelopmental deficits associated with AS.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Analysis of Variance
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Angelman Syndrome / genetics
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Angelman Syndrome / pathology
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Animals
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Animals, Newborn
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Bacterial Proteins / genetics
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Cells, Cultured
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Cerebral Cortex / cytology
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Cerebral Cortex / ultrastructure*
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Cytoplasmic Structures / genetics
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Cytoplasmic Structures / metabolism
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Cytoplasmic Structures / ultrastructure
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Disease Models, Animal
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Embryo, Mammalian
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Female
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Gene Expression Regulation / genetics
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Gene Expression Regulation / physiology
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Glycine / analogs & derivatives
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Golgi Apparatus / genetics*
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Golgi Apparatus / pathology*
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Golgi Apparatus / ultrastructure
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Green Fluorescent Proteins / genetics
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HEK293 Cells
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Humans
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Hydrogen-Ion Concentration
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Lectins / metabolism
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Luminescent Proteins / genetics
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Microscopy, Electron, Transmission
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Mutagenesis
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N-Acetylneuraminic Acid / metabolism*
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Neurons / metabolism
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Neurons / ultrastructure
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Protein Transport / genetics
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Spermine / analogs & derivatives
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Transfection
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Ubiquitin-Protein Ligases / deficiency
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Ubiquitin-Protein Ligases / metabolism*
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Vesicle-Associated Membrane Protein 2 / genetics
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Vesicle-Associated Membrane Protein 2 / metabolism
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Viral Proteins / genetics
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Viral Proteins / metabolism
Substances
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Bacterial Proteins
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Lectins
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Luminescent Proteins
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RNA, Small Interfering
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Vesicle-Associated Membrane Protein 2
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Viral Proteins
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yellow fluorescent protein, Bacteria
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dioctadecylamidoglycylspermine
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Green Fluorescent Proteins
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Spermine
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Ube3a protein, mouse
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Ubiquitin-Protein Ligases
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N-Acetylneuraminic Acid
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Glycine