The essential role of E3 ubiquitin ligases in the pathogenesis of neurodevelopmental and psychiatric disorders: Cul3, Cul4, Ube3a, and ZNRF1

The ubiquitin-proteasome system (UPS) is a crucial proteolytic pathway responsible for maintaining cellular homeostasis by degrading specific substrates and misfolded proteins. Protein ubiquitination, a key post-translational modification, is mediated by three enzymes: E1 (activating enzyme), E2 (conjugating enzyme), and E3 (ligase enzyme). Among these, E3 ligase genes have been linked to various neurological disorders, emphasizing the need to understand their molecular mechanisms. This paper reviews recent studies on the substrates of various E3 ubiquitin ligases including Cul3, Cul4, Ube3a, and ZNRF1, and explains how their dysfunction contributes to neuronal impairments and disease phenotypes. By deepening our understanding of these mechanisms, this review aims to facilitate the development of targeted therapies and guide future research into neurodegenerative and neurodevelopmental disorders.