S-Palmitoylation of Synaptic Proteins in Neuronal Plasticity in Normal and Pathological Brains

Abstract

Protein lipidation is a common post-translational modification of proteins that plays an important role in human physiology and pathology. One form of protein lipidation, S-palmitoylation, involves the addition of a 16-carbon fatty acid (palmitate) onto proteins. This reversible modification may affect the regulation of protein trafficking and stability in membranes. From multiple recent experimental studies, a picture emerges whereby protein S-palmitoylation is a ubiquitous yet discrete molecular switch enabling the expansion of protein functions and subcellular localization in minutes to hours. Neural tissue is particularly rich in proteins that are regulated by S-palmitoylation. A surge of novel methods of detection of protein lipidation at high resolution allowed us to get better insights into the roles of protein palmitoylation in brain physiology and pathophysiology. In this review, we specifically discuss experimental work devoted to understanding the impact of protein palmitoylation on functional changes in the excitatory and inhibitory synapses associated with neuronal activity and neuronal plasticity. The accumulated evidence also implies a crucial role of S-palmitoylation in learning and memory, and brain disorders associated with impaired cognitive functions.

Keywords: S-palmitoylation; brain disorders; learning and memory; synaptic plasticity.

Figure 1

Symbolic illustration of the palmitoylation/depalmitoylation cycle with key enzymes and their inhibitors. S-palmitoylation of the substrate protein is preceded by the auto-acylation of the ZDHHC enzymes (middle panel). The palmitoyl group is moved from the palmitoyl-CoA molecule onto the cysteine residue of ZDHHC, creating an intermediate state. Then, the fatty acyl group is moved into the thiol group of a cysteine residue of a substrate protein (right panel). The reverse process of removing the palmitoyl group from protein (depalmitoylation) is catalyzed by palmitoyl-protein thioesterases (left panel). The inhibitors of enzymes are shown in purple oval boxes. Abbreviations: NtBuHA, N-(tert-butyl) hydroxylamine; APT1, acyl-protein thioesterase 1; APT2, acyl-protein thioesterase 2; APT1L, APT1-like; PPT1, palmitoyl-protein thioesterase 1; PPT2, palmitoyl-protein thioesterase 2; ZDHHC, zinc finger DHHCs; CoA, coenzyme A; 2-BP, 2-bromopalmitate; CMA, cyano-myracrylamide; C, cysteine residue.

Figure 2

Schematic illustration of the proteins and enzymes of the palmitoylation machinery mentioned in this review in the context of function and plasticity of inhibitory and excitatory synapse. Synaptic proteins in the inhibitory (left) and excitatory (middle) synapses are symbolically depicted, together with palmitoyltransferases (green) and depalmitoylating enzymes (red). The right panel shows proteins (gray) that undergo neuronal activity-dependent palmitoylation and could potentially be involved in the regulation of the function or plasticity of the excitatory synapses (putative candidates not yet confirmed with functional experiments). APT1, acyl-protein thioesterase 1; PPT1, palmitoyl-protein thioesterase 1; ABHD17, alpha/beta hydrolase domain-containing proteins 17; ZDHHC, zinc finger DHHCs; GABA_AR, GABA_A receptor; AMPAR, AMPA receptor; NMDAR, NMDA receptor; PSD-95, Postsynaptic density protein 95; PICK1, protein interacting with C-kinase; AKAP79/150, A-kinase anchoring protein 79/150; ABP, AMPA receptor binding protein; GRIP1, glutamate receptor interacting protein-1; Arc, activity-regulated cytoskeletal-associated protein; VAMP, vesicle-associated membrane protein; SNAP25, synaptosomal-associated protein 25; SynDIG1, synapse differentiation Inducing 1 protein; PRG-1, plasticity-related gene 1 protein; Cdc42, cell division control protein 42 homo.log.