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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.

Pubmed ID: 20211139


  • Greer PL
  • Hanayama R
  • Bloodgood BL
  • Mardinly AR
  • Lipton DM
  • Flavell SW
  • Kim TK
  • Griffith EC
  • Waldon Z
  • Maehr R
  • Ploegh HL
  • Chowdhury S
  • Worley PF
  • Steen J
  • Greenberg ME



Publication Data

March 5, 2010

Associated Grants

  • Agency: NIMH NIH HHS, Id: MH53608
  • Agency: NINDS NIH HHS, Id: NS28829
  • Agency: NINDS NIH HHS, Id: R01 NS028829
  • Agency: NINDS NIH HHS, Id: R01 NS028829-19
  • Agency: NINDS NIH HHS, Id: R01 NS028829-20
  • Agency: NINDS NIH HHS, Id: R01 NS028829-21
  • Agency: NINDS NIH HHS, Id: R01 NS028829-21S1

Mesh Terms

  • Angelman Syndrome
  • Animals
  • Cells, Cultured
  • Cognition
  • Cytoskeletal Proteins
  • Humans
  • Mice
  • Mice, Knockout
  • Nerve Tissue Proteins
  • Receptors, AMPA
  • Synapses
  • Ubiquitin-Protein Ligases
  • Ubiquitination