Ube3a Imprinting Impairs Circadian Robustness in Angelman Syndrome Models

Abstract

Summary 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 an 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.

Aberrant Proteostasis of BMAL1 Underlies Circadian Abnormalities in a Paradigmatic mTOR-opathy

“…Interestingly, maternally imprinted Ube3A mouse mutants appear to demonstrate subtle lengthening of circadian period and rapid phase resetting – the former is similar and the latter divergent from the phenotypes we observe in the TSC mouse models(Ehlen et al, 2015; Shi et al, 2015). Thus, while our findings highlight an unexpected potential molecular interaction between Angelman’s syndrome and TSC through the regulation of BMAL1 proteostasis, it is likely that these interactions are likely complex and are consistent with the only partial overlap (e.g.…”

“…Because BMAL1 has been shown to be ubiquitinated by the E3 ligase UBE3A and undergo proteasomal degradation, we hypothesized that the changes in BMAL1 stability in Tsc2−/− cells could be explained by alterations in BMAL1 ubiquitination (Gossan et al, 2014; Sahar et al, 2010; Shi et al, 2015). We treated Tsc2 MEFs with the proteasome inhibitor bortezomib (BTZ) for 4 hours with or without Torin 1.…”

New Perspectives on Genomic Imprinting, an Essential and Multifaceted Mode of Epigenetic Control in the Developing and Adult Brain

“…When placed in constant darkness, mice with Magel2 paternal deletions exhibit abnormal general activity amplitudes across the 24-h period (Kozlov et al 2007). Abnormal periodicity and accelerated adjustment to light/dark changes was documented in Ube3a maternal deletions and is associated with lack of UBE3A-mediated degradation of BMAL1 (Shi et al 2015). Deletions of Peg3 or Kcnk9 cause increased nocturnal activity (Curley et al 2005, Linden et al 2007).…”

Epigenetic Regulation of UBE3A and Roles in Human Neurodevelopmental Disorders

“…UBE3A substrates regulated in the mouse brain by UBE3A include the transcription factor BMAL1, which transcriptionally regulates circadian rhythms and diurnally expressed transcripts in mammals [34]. Regulation of BMAL turnover by UBE3A occurs in the mouse brain and circadian rhythm affected in Ube3a deficient mice [35]. Also of interest for diurnal metabolism is TSC2 [36], a negative modulator of mammalian target of rapamycin (mTOR), which is encoded by a gene mutated in tuberous sclerosis.…”

“…Both Ube3a m-/p+ knockout and UBE3A-Gabrb3 deletion mice showed alterations in circadian rhythms and light/dark entrainment [35]. An even larger mouse deletion including the entire syntenic imprinted region occurred in a transgene insertion line, resulting in the loss of Ube3a in cerebellum when inherited maternally [81].…”