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

Autor: Sell GL; Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Wood Basic Science Building Room 517, 725 N. Wolfe St., Baltimore, MD, 21205, USA. glsell@ucdavis.edu.; Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. glsell@ucdavis.edu.; Center for Neuroscience, University of California-Davis, One Shields Avenue, Davis, CA, 95616, USA. glsell@ucdavis.edu., Xin W; Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.; Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, 21224, USA.; Department of Neurology and the Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, 94158, USA., Cook EK; Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Wood Basic Science Building Room 517, 725 N. Wolfe St., Baltimore, MD, 21205, USA., Zbinden MA; Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Wood Basic Science Building Room 517, 725 N. Wolfe St., Baltimore, MD, 21205, USA.; Human Metabolome Technologies America, Inc., Boston, MA, 02134, USA., Schaffer TB; Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Wood Basic Science Building Room 517, 725 N. Wolfe St., Baltimore, MD, 21205, USA.; NextCure Inc., Beltsville, MD, 20705, USA., O'Meally RN; Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Wood Basic Science Building Room 517, 725 N. Wolfe St., Baltimore, MD, 21205, USA.; Mass Spectrometry and Proteomics Facility, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA., Cole RN; Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Wood Basic Science Building Room 517, 725 N. Wolfe St., Baltimore, MD, 21205, USA.; Mass Spectrometry and Proteomics Facility, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA., Margolis SS; Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Wood Basic Science Building Room 517, 725 N. Wolfe St., Baltimore, MD, 21205, USA. smargol7@jhmi.edu.; Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. smargol7@jhmi.edu.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2021 Sep 30; Vol. 11 (1), pp. 19414. Date of Electronic Publication: 2021 Sep 30.
DOI: 10.1038/s41598-021-97898-w
Abstrakt: 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 can be directly ubiquitylated by UBE3A. 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.
(© 2021. The Author(s).)
Databáze: MEDLINE
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