AUTHOR=Camões dos Santos João , Appleton Carolina , Cazaux Mateus Francisca , Covas Rita , Bekman Evguenia Pavlovna , da Rocha Simão Teixeira 

TITLE=Stem cell models of Angelman syndrome

JOURNAL=Frontiers in Cell and Developmental Biology

VOLUME=11

YEAR=2023

URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2023.1274040

DOI=10.3389/fcell.2023.1274040

ISSN=2296-634X

ABSTRACT=<p>Angelman syndrome (AS) is an imprinted neurodevelopmental disorder that lacks a cure, characterized by developmental delay, intellectual impairment, seizures, ataxia, and paroxysmal laughter. The condition arises due to the loss of the maternally inherited copy of the <italic>UBE3A</italic> gene in neurons. The paternally inherited <italic>UBE3A</italic> allele is unable to compensate because it is silenced by the expression of an antisense transcript (<italic>UBE3A-ATS</italic>) on the paternal chromosome. <italic>UBE3A</italic>, encoding enigmatic E3 ubiquitin ligase variants, regulates target proteins by either modifying their properties/functions or leading them to degradation through the proteasome. Over time, animal models, particularly the <italic>Ube3a</italic><sup>mat−/pat+</sup> Knock-Out (KO) mice, have significantly contributed to our understanding of the molecular mechanisms underlying AS. However, a shift toward human pluripotent stem cell models (PSCs), such as human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), has gained momentum. These stem cell models accurately capture human genetic and cellular characteristics, offering an alternative or a complement to animal experimentation. Human stem cells possess the remarkable ability to recapitulate neurogenesis and generate “brain-in-a-dish” models, making them valuable tools for studying neurodevelopmental disorders like AS. In this review, we provide an overview of the current state-of-the-art human stem cell models of AS and explore their potential to become the preclinical models of choice for drug screening and development, thus propelling AS therapeutic advancements and improving the lives of affected individuals.</p>