Tissue-specific variation of Ube3a protein expression in rodents and in a mouse model of Angelman syndrome

NEUROBIOLOGY OF DISEASE

卷:39

Article

Gustin, Richard M.¹  Bichell, Terry Jo^2,3  Bubser, Michael^1,4  Daily, Jennifer⁵  Filonova, Irina⁵  Mrelashvili, Davit⁶  Deutch, Ariel Y.^1,2,3,4  Colbran, Roger J.^2,3,7  Weeber, Edwin J.^5,8,9  Haas, Kevin F.^2,3,10 

[1] Vanderbilt Univ, Dept Pharmacol, Med Ctr, Nashville, TN 37232 USA

[2] Vanderbilt Univ, Med Ctr, Vanderbilt Brain Inst, Nashville, TN USA

[3] Vanderbilt Univ, Med Ctr, Kennedy Ctr Human Dev, Nashville, TN USA

[4] Vanderbilt Univ, Med Ctr, Dept Psychiat, Nashville, TN USA

[5] Univ S Florida, Dept Mol Physiol & Pharmacol, Tampa, FL USA

[6] Univ S Carolina, Dept Neurol, Columbia, SC 29208 USA

[7] Vanderbilt Univ, Dept Mol Physiol & Biophys, Med Ctr, Nashville, TN 37232 USA

[8] Univ S Florida, Johnnie B Byrd Sr Alzheimers Ctr, Tampa, FL USA

[9] Univ S Florida, Res Inst, Tampa, FL USA

[10] Vanderbilt Univ, Med Ctr, Dept Neurol, Nashville, TN USA

关键词: Angelman syndrome;    Ubiquitin;    Ubiquitin ligase;    E6-AP;    Ube3a;    Genetic imprinting;    Synapse;    Epilepsy;    Thalamocortical;    Interneurons;   

DOI  :  10.1016/j.nbd.2010.04.012

来源: Elsevier

【 摘 要 】

Angelman syndrome (AS) is a neurogenetic disorder caused by loss of maternal UBE3A expression or mutation-induced dysfunction of its protein product, the E3 ubiquitin-protein ligase, UBE3A. In humans and rodents. UBE3A/Ube3a transcript is maternally imprinted in several brain regions, but the distribution of native UBE3A/Ube3a1 protein expression has not been comprehensively examined. To address this, we systematically evaluated Ube3a expression in the brain and peripheral tissues of wild-type (WT) and Ube3a maternal knockout mice (AS mice). Immunoblot and immunohistochemical analyses revealed a marked loss of Ube3a protein in hippocampus, hypothalamus, olfactoiy bulb, cerebral cortex, striatum, thalamus, midbrain, and cerebellum in AS mice relative to WT littermates. Also, Ube3a expression in heart and liver of AS mice showed greater than the predicted 50% reduction relative to WT mice. Co-localization studies showed Ube3a expression to be primarily neuronal in all brain regions and present in GABAergic interneurons as well as principal neurons. These findings suggest that neuronal function throughout the brain is compromised in AS. (C) 2010 Elsevier Inc. All rights reserved.

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