Circadian Rhythms and Sleep Are Dependent Upon Expression Levels of Key Ubiquitin Ligase Ube3a

Abstract

Normal neurodevelopment requires precise expression of the key ubiquitin ligase gene Ube3a. Comparing newly generated mouse models for Ube3a downregulation (models of Angelman syndrome) vs. Ube3a upregulation (models for autism), we find reciprocal effects of Ube3a gene dosage on phenotypes associated with circadian rhythmicity, including the amount of locomotor activity. Consistent with results from neurons in general, we find that Ube3a is imprinted in neurons of the suprachiasmatic nuclei (SCN), the pacemaking circadian brain locus, despite other claims that SCN neurons were somehow exceptional to these imprinting rules. In addition, Ube3a-deficient mice lack the typical drop in wake late in the dark period and have blunted responses to sleep deprivation. Suppression of physical activity by light in Ube3a-deficient mice is not due to anxiety as measured by behavioral tests and stress hormones; quantification of stress hormones may provide a mechanistic link to sleep alteration and memory deficits caused by Ube3a deficiency, and serve as an easily measurable biomarker for evaluating potential therapeutic treatments for Angelman syndrome. We conclude that reduced Ube3a gene dosage affects not only neurodevelopment but also sleep patterns and circadian rhythms.

Antisense oligonucleotide therapy rescues disturbed brain rhythms and sleep in juvenile and adult mouse models of Angelman syndrome

“…Thus, both Ube3a mRNA and proteins are diminished in the Ube3a mΔe6/p+ mouse brains. Furthermore, Ube3a mΔe6/p+ mice showed similar rotarod and marble burying phenotypes to previously reported deficits in Ube3a mΔe5/p+ mice ( Shi et al, 2022 ).…”

“…Despite limited prior successes in rescuing juvenile and adult maternal Ube3a deficiency mice, we chose these two ages to examine the effects of ASO therapy on cortical hyperexcitability, altered EEG power spectrum, and sleep disturbance because these ages are more translationally relevant than the neonatal period. Our study reveals that a single ICV injection of Ube3a-ATS -targeted ASOs to Ube3a mΔe6/p+ mice, a new rodent model of Angelman syndrome ( Shi et al, 2022 ), upregulates Ube3a proteins including the critical short isoform and restores the EEG power spectrum and sleep pattern for at least 6 weeks, particularly upon treatment at the juvenile age. Therefore, our results significantly expand the range of phenotypes that can be reversed by restoring Ube3a expression in juvenile and adult mice.…”

Reanalysis of primate brain circadian transcriptomics reveals connectivity-related oscillations

“…Given that organisms require diverse proteins for time-dependent and region-specific functions and protein degradation rates fluctuate widely, robust cycling behavior in gene expression for these pathways is anticipated to match daily cellular activity variations. 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 The malfunction of this pathway due to deficient Ubiquitin ligase (UbL) expression has been linked to disrupted circadian systems and impaired neuropeptide transport in animal UbL knockout models. 58 , 60 , 62 , 63 , 64 , 65 Microtubule-based processes, facilitating intracellular protein transport, were found enriched in most of the same brain regions as this protein regulatory pathway.…”

Death of a Protein: The Role of E3 Ubiquitin Ligases in Circadian Rhythms of Mice and Flies

“…It is also the causative gene for the neurodevelopmental disorder Angelman Syndrome (AS), in which UBE3A expression is absent due to the loss of the maternal allele amid the normally silenced paternal allele [90]. There is evidence for and against paternal imprinting of the Ube3a gene in SCN neurons [91,92]. Sleep disturbances are one of the symptoms of AS, which include delayed development, intellectual disability, impaired speech, and motor dysfunction [93].…”

“…Sleep disturbances are one of the symptoms of AS, which include delayed development, intellectual disability, impaired speech, and motor dysfunction [93]. Ablating the maternal copy of Ube3a in mice consistently disrupts sleep homeostasis [89,92,94]. However, one study found that this mutation also lengthens the circadian period under constant darkness (DD), accelerates recovery from jetlag (i.e., mice re-entrain more rapidly to an advanced light-dark schedule), and suppresses locomotor activity under constant light (LL), whereas another study found no effect on circadian period [89,95].…”