Ubiquitination in the Nervous System: From Molecular Mechanisms to Disease Implications

The ubiquitin‒proteasome system (UPS) comprises ubiquitin, various enzymes, and the proteasome, which are collectively responsible for selectively regulating protein degradation within the human body. Ubiquitination plays a crucial role in various physiological and pathological processes of the nervous system. In neurons, ubiquitination influences synaptic transmission, neural network formation, and mitochondrial homeostasis. E3 ubiquitin ligases (E3s) such as ubiquitin-protein ligase E3A (UBE3A), HUWE1, and Parkin, along with deubiquitinating enzymes (DUBs) such as USP9X (ubiquitin specific peptidase 9, X-linked) and OTUD5, are vital for neural development and functional maintenance. The dysregulation of ubiquitination is closely associated with neurodegenerative diseases such as Parkinson's disease (PD) and Alzheimer's disease (AD). A comprehensive understanding of the functions of ubiquitination in the nervous system and an in-depth exploration of its mechanisms in neural development and disease progression may reveal potential targets and therapeutic strategies for treating neurodegenerative disorders.