title: Ube3a imprinting impairs circadian robustness in Angelman syndrome models.
abstract: 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.
authors: Department of Biological Sciences, Vanderbilt University, Nashville, TN 37235, USA.
authors: Shu-qun
authors: SQ
authors: Shi
authors: Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN 37235, USA.
authors: Terry Jo
authors: TJ
authors: Bichell
authors: Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN 37235, USA; Cancer Biology, Vanderbilt University, Nashville, TN 37235, USA.
authors: Rebecca A
authors: RA
authors: Ihrie
authors: Department of Biological Sciences, Vanderbilt University, Nashville, TN 37235, USA; Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN 37235, USA; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37235, USA. Electronic address: carl.h.johnson@vanderbilt.edu.
authors: Carl Hirschie
authors: CH
authors: Johnson
mesh_terms: D056930:ARNTL Transcription Factors / Q000378:metabolism; D000704:Analysis of Variance; D017204:Angelman Syndrome / Q000235:genetics / Q000503:physiopathology*; D000818:Animals; D001835:Body Weight / Q000502:physiology; D019454:Chronotherapy / Q000379:methods; D002940:Circadian Rhythm / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D017353:Gene Deletion; D018392:Genomic Imprinting / Q000235:genetics*; D006801:Humans; D008099:Liver / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000378:metabolism*; D012893:Sleep Wake Disorders / Q000628:therapy; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; C502429:Ube3a protein, mouse; D044767:Ubiquitin-Protein Ligases