Skip to main content
bioRxiv
  • Home
  • About
  • Submit
  • ALERTS / RSS
Advanced Search
New Results

Deleting a UBE3A substrate rescues impaired hippocampal physiology and learning in Angelman syndrome mice

Gabrielle L. Sell, Wendy Xin, Emily K. Cook, Mark A. Zbinden, Thomas B. Schaffer, Robert N. O’Meally, Robert N. Cole, Antonello Bonci, Seth S. Margolis
doi: https://doi.org/10.1101/625418
Gabrielle L. Sell
1Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
2Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Wendy Xin
2Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
3Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Emily K. Cook
1Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Mark A. Zbinden
1Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Thomas B. Schaffer
1Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Robert N. O’Meally
1Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
5Mass Spectrometry and Proteomics Facility, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Robert N. Cole
1Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
5Mass Spectrometry and Proteomics Facility, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Antonello Bonci
2Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
3Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224, USA
4Department of Psychiatry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Seth S. Margolis
1Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
2Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: smargol7@jhmi.edu
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Preview PDF
Loading

ABSTRACT

In humans, loss-of-function mutations in the UBE3A gene lead to the neurodevelopmental disorder Angelman syndrome (AS). AS patients have severe impairments in speech, learning and memory, and motor coordination, for which there is currently no treatment. In addition, UBE3A is duplicated in >1-2% of patients with autism spectrum disorders – a further indication of the significant role it plays in brain development. Altered expression of UBE3A, an E3 ubiquitin ligase, is hypothesized to lead to impaired levels of its target proteins, but identifying the contribution of individual UBE3A targets to UBE3A-dependent deficits remains of critical importance. Ephexin5 is a putative UBE3A substrate that has restricted expression early in development, regulates synapse formation during hippocampal development, and is abnormally elevated in AS mice, modeled by maternally-derived Ube3a gene deletion. Here, we report that Ephexin5 is a direct substrate of UBE3A ubiquitin ligase activity. Furthermore, removing Ephexin5 from AS mice specifically rescued hippocampus-dependent behaviors, CA1 physiology, and deficits in dendritic spine number. Our findings identify Ephexin5 as a key driver of hippocampal dysfunction and related behavioral deficits in AS mouse models. These results demonstrate the exciting potential of targeting Ephexin5, and possibly other UBE3A substrates, to improve symptoms of AS and other UBE3A-related developmental disorders.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
Back to top
PreviousNext
Posted May 02, 2019.
Download PDF
Email

Thank you for your interest in spreading the word about bioRxiv.

NOTE: Your email address is requested solely to identify you as the sender of this article.

Enter multiple addresses on separate lines or separate them with commas.
Deleting a UBE3A substrate rescues impaired hippocampal physiology and learning in Angelman syndrome mice
(Your Name) has forwarded a page to you from bioRxiv
(Your Name) thought you would like to see this page from the bioRxiv website.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Share
Deleting a UBE3A substrate rescues impaired hippocampal physiology and learning in Angelman syndrome mice
Gabrielle L. Sell, Wendy Xin, Emily K. Cook, Mark A. Zbinden, Thomas B. Schaffer, Robert N. O’Meally, Robert N. Cole, Antonello Bonci, Seth S. Margolis
bioRxiv 625418; doi: https://doi.org/10.1101/625418
Reddit logo Twitter logo Facebook logo LinkedIn logo Mendeley logo
Citation Tools
Deleting a UBE3A substrate rescues impaired hippocampal physiology and learning in Angelman syndrome mice
Gabrielle L. Sell, Wendy Xin, Emily K. Cook, Mark A. Zbinden, Thomas B. Schaffer, Robert N. O’Meally, Robert N. Cole, Antonello Bonci, Seth S. Margolis
bioRxiv 625418; doi: https://doi.org/10.1101/625418

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Subject Area

  • Neuroscience
Subject Areas
All Articles
  • Animal Behavior and Cognition (4863)
  • Biochemistry (10815)
  • Bioengineering (8061)
  • Bioinformatics (27366)
  • Biophysics (14011)
  • Cancer Biology (11154)
  • Cell Biology (16091)
  • Clinical Trials (138)
  • Developmental Biology (8806)
  • Ecology (13320)
  • Epidemiology (2067)
  • Evolutionary Biology (17387)
  • Genetics (11701)
  • Genomics (15954)
  • Immunology (11053)
  • Microbiology (26139)
  • Molecular Biology (10673)
  • Neuroscience (56691)
  • Paleontology (422)
  • Pathology (1737)
  • Pharmacology and Toxicology (3012)
  • Physiology (4563)
  • Plant Biology (9661)
  • Scientific Communication and Education (1617)
  • Synthetic Biology (2696)
  • Systems Biology (6989)
  • Zoology (1512)