S-acylation and neuroinflammation: the therapeutic potential of zDHHC and deacylase modulation

Neuroinflammation is a hallmark of many neurodegenerative diseases, including Alzheimer's, Parkinson's and Huntington's disease, multiple sclerosis, and infantile neuronal ceroid lipofuscinosis. Dynamic protein S-acylation, a reversible lipid post-translational modification, is an important regulator in these processes. S-acylation is catalysed by the zDHHC palmitoyl acyltransferases, and removal of the acyl groups is mediated by acyl-protein thioesterases. S-acylation controls the localisation, stability, and function of around 48 % of all proteins in the nervous system, including synaptic scaffolds, ion channels, immune receptors, and trafficking proteins. Moreover, dysregulated S-acylation contributes to synaptic loss, aberrant immune signalling, and neurodegeneration. This review examines proteins implicated in neuroinflammation with reported S-acylase or deacylase activity, outlines current knowledge on disease-related alterations in S-acylation, and assesses the therapeutic promise of available small-molecule modulators. Linking the activity of these enzymes with human disease highlights the potential of reversible S-acylation as a source of innovative targets for drug discovery in neuroinflammation.