Protein palmitoylation: biological functions, disease, and therapeutic targets

Protein palmitoylation, a reversible post-translational lipid modification, is catalyzed by the ZDHHC family of palmitoyltransferases and reversed by several acyl protein thioesterases, regulating protein localization, accumulation, secretion, and function. Neurological disorders encompass a spectrum of diseases that affect both the central and peripheral nervous system. Recently, accumulating studies have revealed that pathological protein associated with neurological diseases, such as β-amyloid, α-synuclein, and Huntingtin, could undergo palmitoylation, highlighting the crucial roles of protein palmitoylation in the onset and development of neurological diseases. However, few preclinical studies and clinical trials focus on the interventional strategies that target protein palmitoylation. Here, we comprehensively reviewed the emerging evidence on the role of protein palmitoylation in various neurological diseases and summarized the classification, processes, and functions of protein palmitoylation, highlighting its impact on protein stability, membrane localization, protein–protein interaction, as well as signal transduction. Furthermore, we also discussed the potential interventional strategies targeting ZDHHC proteins and elucidated their underlying pathogenic mechanisms in neurological diseases. Overall, an in-depth understanding of the functions and significances of protein palmitoylation provide new avenues for investigating the mechanisms and therapeutic approaches for neurological disorders.