NERL2 (neuralized E3 ubiquitin protein ligase 2) is an E3 ubiquitin ligase adaptor that plays a critical role in myofiber differentiation and maturation. As a component of an SCF-like ECS ubiquitin-protein ligase complex, NEURL2 mediates substrate ubiquitination and degradation, with particular importance for controlling sarcolemmal beta-catenin levels during myogenesis 1. During myofibril assembly, NEURL2 regulates beta-catenin degradation at the sarcolemma, which is essential for proper sarcomeric organization and myofiber maturation 2. Beyond muscle development, NEURL2 interacts with Notch signaling ligands, including Delta-like1 and Delta-like4, functioning as a developmental regulator with prominent expression during embryonic brain development 3. NEURL2 has significant disease relevance in motor neuron disorders; genome-wide RNAi screening identified NEURL2 as an E3 ligase that cooperatively works with Mib1 to ubiquitinate and promote survival motor neuron (SMN) protein degradation 4. This mechanism is relevant to spinal muscular atrophy (SMA) pathogenesis, suggesting NEURL2 inhibition could represent a therapeutic strategy to increase SMN levels and improve motor outcomes in SMA patients, complementing current SMN-elevating therapies.