Ube3a-KO Mouse

The UBE3A gene encodes ubiquitin-protein ligase E3A, a critical enzyme in the ubiquitin-proteasome degradation system responsible for catalyzing substrate ubiquitination and regulating proteasomal clearance. This process is indispensable for maintaining proteostasis, particularly in neurons, where UBE3A governs synaptic plasticity, neural signaling, and neurodevelopment by modulating the levels of specific substrates. As an imprinted gene, UBE3A exhibits parent-of-origin-specific expression in brain neurons. The paternal allele is epigenetically silenced via cis-acting repression by a long noncoding antisense transcript (UBE3A-ATS) ^[1]. Consequently, only the maternal UBE3A allele is functionally active in neuronal populations. Loss of maternal UBE3A function disrupts ubiquitin-mediated proteolysis, leading to aberrant accumulation of neurodevelopmental regulators and subsequent dysregulation of synaptic maturation and circuit formation. These molecular deficits underlie the pathogenesis of Angelman syndrome (AS), a severe neurogenetic disorder. Patients with Angelman Syndrome commonly exhibit severe motor and intellectual developmental delays, ataxia, hypotonia, epilepsy, speech impairment, and distinctive facial features ^[2].

Currently, there is no curative treatment for Angelman Syndrome. Management primarily focuses on comprehensive rehabilitation aimed at alleviating symptoms and improving quality of life. Therapeutic development is centered on long-acting, precisely targeted, and safe approaches. Some therapies have entered clinical trial stages, mainly including: gene therapy (UBE3A gene supplementation via viral vectors), paternal UBE3A gene reactivation (utilizing ASOs, CRISPR, etc., to target silencing long noncoding RNAs and unsilencing the gene), pathway intervention (such as OV101 to modulate neuronal over-inhibition), and symptomatic treatment (such as optimizing anti-epileptic drugs) ^[3-4].

Mice and humans share a high degree of similarity in the UBE3A gene region, and paternal imprinting of the Ube3a gene also exists in mice ^[5-6]. Studies have shown that knocking out the maternal Ube3a allele in mice also leads to phenotypes similar to human Angelman Syndrome (AS), including motor deficits, cognitive impairment, epilepsy susceptibility, sleep disturbances, and anxiety-like behaviors. Therefore, these mice are widely used in disease research, gene therapy evaluation, drug screening, and early intervention studies ^[5-6]. The Ube3a-KO mouse is a gene knockout (KO) model, generated using gene editing technology to knock out the protein-coding sequence of the Ube3a gene (the homologous gene of human UBE3A gene) in mice. Preliminary behavioral data indicate that this model exhibits anxiety-like/compulsive behaviors, abnormal stress responses, and is accompanied by decreased spontaneous activity, shortened movement distance, and reduced average motility, among other motor function and behavioral abnormalities. It can be used for research on the pathogenesis of Angelman Syndrome (AS) and the development of related therapies.