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

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...

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Autores principales:	Gabrielle L. Sell, Wendy Xin, Emily K. Cook, Mark A. Zbinden, Thomas B. Schaffer, Robert N. O’Meally, Robert N. Cole, Seth S. Margolis
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/65582c1636854f608ecc07c0e17a093b
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spelling	oai:doaj.org-article:65582c1636854f608ecc07c0e17a093b2021-12-02T18:51:14ZDeleting a UBE3A substrate rescues impaired hippocampal physiology and learning in Angelman syndrome mice10.1038/s41598-021-97898-w2045-2322https://doaj.org/article/65582c1636854f608ecc07c0e17a093b2021-09-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-97898-whttps://doaj.org/toc/2045-2322Abstract 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.Gabrielle L. SellWendy XinEmily K. CookMark A. ZbindenThomas B. SchafferRobert N. O’MeallyRobert N. ColeSeth S. MargolisNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-16 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Gabrielle L. Sell Wendy Xin Emily K. Cook Mark A. Zbinden Thomas B. Schaffer Robert N. O’Meally Robert N. Cole Seth S. Margolis Deleting a UBE3A substrate rescues impaired hippocampal physiology and learning in Angelman syndrome mice
description	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 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.
format	article
author	Gabrielle L. Sell Wendy Xin Emily K. Cook Mark A. Zbinden Thomas B. Schaffer Robert N. O’Meally Robert N. Cole Seth S. Margolis
author_facet	Gabrielle L. Sell Wendy Xin Emily K. Cook Mark A. Zbinden Thomas B. Schaffer Robert N. O’Meally Robert N. Cole Seth S. Margolis
author_sort	Gabrielle L. Sell
title	Deleting a UBE3A substrate rescues impaired hippocampal physiology and learning in Angelman syndrome mice
title_short	Deleting a UBE3A substrate rescues impaired hippocampal physiology and learning in Angelman syndrome mice
title_full	Deleting a UBE3A substrate rescues impaired hippocampal physiology and learning in Angelman syndrome mice
title_fullStr	Deleting a UBE3A substrate rescues impaired hippocampal physiology and learning in Angelman syndrome mice
title_full_unstemmed	Deleting a UBE3A substrate rescues impaired hippocampal physiology and learning in Angelman syndrome mice
title_sort	deleting a ube3a substrate rescues impaired hippocampal physiology and learning in angelman syndrome mice
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/65582c1636854f608ecc07c0e17a093b
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Deleting a UBE3A substrate rescues impaired hippocampal physiology and learning in Angelman syndrome mice

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