title: The Angelman syndrome protein Ube3a/E6AP is required for Golgi acidification and surface protein sialylation.
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.
authors: Department of Neurobiology, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors: Kathryn H
authors: KH
authors: Condon
authors: Jianghai
authors: J
authors: Ho
authors: Camenzind G
authors: CG
authors: Robinson
authors: Cyril
authors: C
authors: Hanus
authors: Michael D
authors: MD
authors: Ehlers
mesh_terms: D000704:Analysis of Variance; D017204:Angelman Syndrome / Q000235:genetics / Q000473:pathology; D000818:Animals; D000831:Animals, Newborn; D001426:Bacterial Proteins / Q000235:genetics; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000648:ultrastructure*; D022083:Cytoplasmic Structures / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology; D005998:Glycine / Q000031:analogs & derivatives; D006056:Golgi Apparatus / Q000235:genetics* / Q000473:pathology* / Q000648:ultrastructure; D049452:Green Fluorescent Proteins / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D037102:Lectins / Q000378:metabolism; D008164:Luminescent Proteins / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D016296:Mutagenesis; D019158:N-Acetylneuraminic Acid / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism / Q000648:ultrastructure; D021381:Protein Transport / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D013096:Spermine / Q000031:analogs & derivatives; D014162:Transfection; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000378:metabolism*; D050988:Vesicle-Associated Membrane Protein 2 / Q000235:genetics / Q000378:metabolism; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D037102:Lectins; D008164:Luminescent Proteins; D034741:RNA, Small Interfering; D050988:Vesicle-Associated Membrane Protein 2; D014764:Viral Proteins; C054562:yellow fluorescent protein, Bacteria; C061134:dioctadecylamidoglycylspermine; D049452:Green Fluorescent Proteins; D013096:Spermine; C502429:Ube3a protein, mouse; D044767:Ubiquitin-Protein Ligases; D019158:N-Acetylneuraminic Acid; D005998:Glycine