Ube3a imprinting impairs circadian robustness in Angelman syndrome models.

Shi SQ, Bichell TJ, Ihrie RA, Johnson CH
Curr Biol. 2015 25 (5): 537-45

PMID: 25660546 · PMCID: PMC4348236 · DOI:10.1016/j.cub.2014.12.047

BACKGROUND - The paternal allele of Ube3a is silenced by imprinting in neurons, and Angelman syndrome (AS) is a disorder arising from a deletion or mutation of the maternal Ube3a allele, which thereby eliminates Ube3a neuronal expression. Sleep disorders such as short sleep duration and increased sleep onset latency are very common in AS.

RESULTS - We found a unique link between neuronal imprinting of Ube3a and circadian rhythms in two mouse models of AS, including enfeebled circadian activity behavior and slowed molecular rhythms in ex vivo brain tissues. As a consequence of compromised circadian behavior, metabolic homeostasis is also disrupted in AS mice. Unsilencing the paternal Ube3a allele restores functional circadian periodicity in neurons deficient in maternal Ube3a but does not affect periodicity in peripheral tissues that are not imprinted for uniparental Ube3a expression. The ubiquitin ligase encoded by Ube3a interacts with the central clock components BMAL1 and BMAL2. Moreover, inactivation of Ube3a expression elevates BMAL1 levels in brain regions that control circadian behavior of AS-model mice, indicating an important role for Ube3a in modulating BMAL1 turnover.

CONCLUSIONS - Ube3a expression constitutes a direct mechanistic connection between symptoms of a human neurological disorder and the central circadian clock mechanism. The lengthened circadian period leads to delayed phase, which could explain the short sleep duration and increased sleep onset latency of AS subjects. Moreover, we report the pharmacological rescue of an AS phenotype, in this case, altered circadian period. These findings reveal potential treatments for sleep disorders in AS patients.

Copyright © 2015 Elsevier Ltd. All rights reserved.

MeSH Terms (15)

Analysis of Variance Angelman Syndrome Animals ARNTL Transcription Factors Body Weight Chronotherapy Circadian Rhythm Gene Deletion Genomic Imprinting Humans Liver Mice Neurons Sleep Wake Disorders Ubiquitin-Protein Ligases

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