RT Journal Article
SR Electronic
T1 The Angelman Syndrome Protein Ube3a/E6AP Is Required for Golgi Acidification and Surface Protein Sialylation
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 3799
OP 3814
DO 10.1523/JNEUROSCI.1930-11.2013
VO 33
IS 9
A1 Condon, Kathryn H.
A1 Ho, Jianghai
A1 Robinson, Camenzind G.
A1 Hanus, Cyril
A1 Ehlers, Michael D.
YR 2013
UL http://www.jneurosci.org/content/33/9/3799.abstract
AB 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 (UBE3Am−/p+) mice. In Ube3a knockdown cell lines and UBE3Am−/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.