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PMID:23447592

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Citation

Condon, KH, Ho, J, Robinson, CG, Hanus, C and Ehlers, MD (2013) The Angelman syndrome protein Ube3a/E6AP is required for Golgi acidification and surface protein sialylation. J. Neurosci. 33:3799-814

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.

Links

PubMed PMC3783510 Online version:10.1523/JNEUROSCI.1930-11.2013

Keywords

Analysis of Variance; Angelman Syndrome/genetics; Angelman Syndrome/pathology; Animals; Animals, Newborn; Bacterial Proteins/genetics; Cells, Cultured; Cerebral Cortex/cytology; Cerebral Cortex/ultrastructure; Cytoplasmic Structures/genetics; Cytoplasmic Structures/metabolism; Cytoplasmic Structures/ultrastructure; Disease Models, Animal; Embryo, Mammalian; Female; Gene Expression Regulation/genetics; Gene Expression Regulation/physiology; Glycine/analogs & derivatives; Golgi Apparatus/genetics; Golgi Apparatus/pathology; Golgi Apparatus/ultrastructure; Green Fluorescent Proteins/genetics; HEK293 Cells; Humans; Hydrogen-Ion Concentration; Lectins/metabolism; Luminescent Proteins/genetics; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Microscopy, Electron, Transmission; Mutagenesis; N-Acetylneuraminic Acid/metabolism; Neurons/metabolism; Neurons/ultrastructure; Protein Transport/genetics; RNA, Small Interfering/genetics; RNA, Small Interfering/metabolism; Spermine/analogs & derivatives; Transfection; Ubiquitin-Protein Ligases/deficiency; Ubiquitin-Protein Ligases/metabolism; Vesicle-Associated Membrane Protein 2/genetics; Vesicle-Associated Membrane Protein 2/metabolism; Viral Proteins/genetics; Viral Proteins/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:UBE3A

GO:1905528: positive regulation of Golgi lumen acidification

ECO:0000315:

P

A fluorometric assay was used to determine Golgi lumen pH in Ube3a-deficient mouse neurons as compared to the wild type. Figure 5B shows the calibration curve used to convert YFP:CFP intensity ratio to pH; Figure 5G shows the fluorescence intensity and figure 5H shows the pH as calculated using the calibration curve.

complete
CACAO 12116

RAT:F1M7B8

GO:1905528: positive regulation of Golgi lumen acidification

ECO:0000315:

P

A fluorometric assay was used to determine Golgi lumen pH in Ube3a-knockdown rat cells as compared to control. Figure 5B shows the calibration curve used to convert YFP:CFP intensity ratio to pH; Figure D shows the fluorescence intensity and figure 5E shows the pH as calculated using the calibration curve.

complete
CACAO 12146

Notes

See also

References

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