The Angelman Syndrome protein Ube3A regulates synapse development by ubiquitinating arc.
Angelman Syndrome is a debilitating neurological disorder caused by mutation of the E3 ubiquitin ligase Ube3A, a gene whose mutation has also recently been associated with autism spectrum disorders (ASDs). The function of Ube3A during nervous system development and how Ube3A mutations give rise to cognitive impairment in individuals with Angleman Syndrome and ASDs are not clear. We report here that experience-driven neuronal activity induces Ube3A transcription and that Ube3A then regulates excitatory synapse development by controlling the degradation of Arc, a synaptic protein that promotes the internalization of the AMPA subtype of glutamate receptors. We find that disruption of Ube3A function in neurons leads to an increase in Arc expression and a concomitant decrease in the number of AMPA receptors at excitatory synapses. We propose that this deregulation of AMPA receptor expression at synapses may contribute to the cognitive dysfunction that occurs in Angelman Syndrome and possibly other ASDs.
Greer
Paul L
PL
Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115, USA.
Hanayama
Rikinari
R
Bloodgood
Brenda L
BL
Mardinly
Alan R
AR
Lipton
David M
DM
Flavell
Steven W
SW
Kim
Tae-Kyung
TK
Griffith
Eric C
EC
Waldon
Zachary
Z
Maehr
Rene
R
Ploegh
Hidde L
HL
Chowdhury
Shoaib
S
Worley
Paul F
PF
Steen
Judith
J
Greenberg
Michael E
ME
D017204:Angelman Syndrome / Q000503:physiopathology*; D000818:Animals; D002478:Cells, Cultured; D003071:Cognition; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D018091:Receptors, AMPA / Q000378:metabolism; D013569:Synapses / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination
D003598:Cytoskeletal Proteins; D009419:Nerve Tissue Proteins; D018091:Receptors, AMPA; C092069:activity regulated cytoskeletal-associated protein; C502429:Ube3a protein, mouse; D044767:Ubiquitin-Protein Ligases