The Angelman Syndrome Protein Ube3A Regulates Synapse Development by Ubiquitinating Arc

Paul L. Greer, Rikinari Hanayama, Brenda L. Bloodgood, Alan R. Mardinly, David M. Lipton, Steven W. Flavell, Tae Kyung Kim, Eric C. Griffith, Zachary Waldon, Rene Maehr, Hidde L. Ploegh, Shoaib Chowdhury, Paul F. Worley, Judith Steen, Michael E. Greenberg

Research output: Contribution to journalArticle

374 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)704-716
Number of pages13
JournalCell
Volume140
Issue number5
DOIs
StatePublished - Mar 5 2010

Fingerprint

Angelman Syndrome
AMPA Receptors
Synapses
Mutation
Ubiquitin-Protein Ligases
Deregulation
Glutamate Receptors
Neurology
Transcription
Neurons
Proteins
Genes
Nervous System Diseases
Degradation
Nervous System
Autism Spectrum Disorder
Cognitive Dysfunction

Keywords

  • HUMDISEASE
  • MOLNEURO

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Greer, P. L., Hanayama, R., Bloodgood, B. L., Mardinly, A. R., Lipton, D. M., Flavell, S. W., ... Greenberg, M. E. (2010). The Angelman Syndrome Protein Ube3A Regulates Synapse Development by Ubiquitinating Arc. Cell, 140(5), 704-716. https://doi.org/10.1016/j.cell.2010.01.026

The Angelman Syndrome Protein Ube3A Regulates Synapse Development by Ubiquitinating Arc. / Greer, Paul L.; Hanayama, Rikinari; Bloodgood, Brenda L.; Mardinly, Alan R.; Lipton, David M.; Flavell, Steven W.; Kim, Tae Kyung; Griffith, Eric C.; Waldon, Zachary; Maehr, Rene; Ploegh, Hidde L.; Chowdhury, Shoaib; Worley, Paul F.; Steen, Judith; Greenberg, Michael E.

In: Cell, Vol. 140, No. 5, 05.03.2010, p. 704-716.

Research output: Contribution to journalArticle

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 2010, 'The Angelman Syndrome Protein Ube3A Regulates Synapse Development by Ubiquitinating Arc', Cell, vol. 140, no. 5, pp. 704-716. https://doi.org/10.1016/j.cell.2010.01.026
Greer PL, Hanayama R, Bloodgood BL, Mardinly AR, Lipton DM, Flavell SW et al. The Angelman Syndrome Protein Ube3A Regulates Synapse Development by Ubiquitinating Arc. Cell. 2010 Mar 5;140(5):704-716. https://doi.org/10.1016/j.cell.2010.01.026
Greer, Paul L. ; Hanayama, Rikinari ; Bloodgood, Brenda L. ; Mardinly, Alan R. ; Lipton, David M. ; Flavell, Steven W. ; Kim, Tae Kyung ; Griffith, Eric C. ; Waldon, Zachary ; Maehr, Rene ; Ploegh, Hidde L. ; Chowdhury, Shoaib ; Worley, Paul F. ; Steen, Judith ; Greenberg, Michael E. / The Angelman Syndrome Protein Ube3A Regulates Synapse Development by Ubiquitinating Arc. In: Cell. 2010 ; Vol. 140, No. 5. pp. 704-716.
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