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

doi:10.1016/j.cell.2010.01.026

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 journal › Article › peer-review

502 Scopus citations

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 language	English (US)
Pages (from-to)	704-716
Number of pages	13
Journal	Cell
Volume	140
Issue number	5
DOIs	https://doi.org/10.1016/j.cell.2010.01.026
State	Published - Mar 5 2010

Keywords

HUMDISEASE
MOLNEURO

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.cell.2010.01.026

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Greer, P. L., Hanayama, R., Bloodgood, B. L., Mardinly, A. R., Lipton, D. M., Flavell, S. W., Kim, T. K., Griffith, E. C., Waldon, Z., Maehr, R., Ploegh, H. L., Chowdhury, S., Worley, P. F., Steen, J., & 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

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title = "The Angelman Syndrome Protein Ube3A Regulates Synapse Development by Ubiquitinating Arc",

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.",

keywords = "HUMDISEASE, MOLNEURO",

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

note = "Funding Information: We thank S. Margolis for sharing unpublished results and C. Chen, J. Zieg, and S. Cohen for helpful discussions; J. Zieg for assistance with figure making; K. Condon and M. Ehlers for their generous advice on culturing Ube3A knockout neurons; R. Greenberg for assistance with enriched environment experiments; and E. Bennechi for sectioning array tomography ribbons. This research was supported by a National Science Foundation predoctoral fellowship (P.L.G), a Human Frontier Science Program Fellowship (R.H.), a grant from the National Institute of Mental Health (MH53608 to P.F.W), an AS Foundation grant during the initial stages of this work, and a National Institutes of Health grant (NS28829) (M.E.G). ",

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AU - Greer, Paul L.

AU - Hanayama, Rikinari

AU - Bloodgood, Brenda L.

AU - Mardinly, Alan R.

AU - Lipton, David M.

AU - Flavell, Steven W.

AU - Kim, Tae Kyung

AU - Griffith, Eric C.

AU - Waldon, Zachary

AU - Maehr, Rene

AU - Ploegh, Hidde L.

AU - Chowdhury, Shoaib

AU - Worley, Paul F.

AU - Steen, Judith

AU - Greenberg, Michael E.

N1 - Funding Information: We thank S. Margolis for sharing unpublished results and C. Chen, J. Zieg, and S. Cohen for helpful discussions; J. Zieg for assistance with figure making; K. Condon and M. Ehlers for their generous advice on culturing Ube3A knockout neurons; R. Greenberg for assistance with enriched environment experiments; and E. Bennechi for sectioning array tomography ribbons. This research was supported by a National Science Foundation predoctoral fellowship (P.L.G), a Human Frontier Science Program Fellowship (R.H.), a grant from the National Institute of Mental Health (MH53608 to P.F.W), an AS Foundation grant during the initial stages of this work, and a National Institutes of Health grant (NS28829) (M.E.G).

PY - 2010/3/5

Y1 - 2010/3/5

N2 - 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.

AB - 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.

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JF - Cell

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The Angelman Syndrome Protein Ube3A Regulates Synapse Development by Ubiquitinating Arc

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Keywords

ASJC Scopus subject areas

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