Altered Protein Palmitoylation as Disease Mechanism in Neurodegenerative Disorders

Abstract

Palmitoylation, a lipid-based posttranslational protein modification, plays a crucial role in regulating various aspects of neuronal function through altering protein membrane-targeting, stabilities, and protein-protein interaction profiles. Disruption of palmitoylation has recently garnered attention as disease mechanism in neurodegeneration. Many proteins implicated in neurodegenerative diseases and associated neuronal dysfunction, including but not limited to amyloid precursor protein, β-secretase (BACE1), postsynaptic density protein 95, Fyn, synaptotagmin-11, mutant huntingtin, and mutant superoxide dismutase 1, undergo palmitoylation, and recent evidence suggests that altered palmitoylation contributes to the pathological characteristics of these proteins and associated disruption of cellular processes. In addition, dysfunction of enzymes that catalyze palmitoylation and depalmitoylation has been connected to the development of neurological disorders. This review highlights some of the latest advances in our understanding of palmitoylation regulation in neurodegenerative diseases and explores potential therapeutic implications.

Keywords: neurodegeneration; palmitoylation.

Figure 1.

Mechanisms and consequences of protein palmitoylation. A, Protein palmitoylation occurs through dynamic palmitoylation and depalmitoylation cycles. A PAT uses palmitoyl-CoA as a donor to transfer palmitate to the thiol group of a cysteine (C) in substrate proteins. This process is reversed by APT, PPT, as well as ABHD proteins. B, Palmitoylation changes protein function by altering its affinity for membranes and other proteins, regulating its half-life and guiding its trafficking between different subcellular locations. C, Palmitoylation critically influences neuronal function throughout the life span of a neuron. Created with BioRender.com.

Figure 2.

Palmitoylation regulates key proteins and processes involved in neurodegeneration. A, APP processing and accelerated Aβ production. APP is synthesized in the ER and transported in a canonical secretory pathway via Golgi to the PM, where it is processed to form Aβ. Palmitoylation enables APP to enter endosomes, where it undergoes accelerated amyloidogenic processing in LRs due to the presence of palmitoylated BACE1 and γ-secretase. Palmitoylated APP is also enriched in LR-like MAMs that contain BACE1/γ-secretase and generate large amounts of Aβ before releasing it into the extracellular matrix. Finally, a noncanonical MAM-dependent pathway might aid in increased Aβ release via yet-unknown mechanisms. B, Aβ-mediated synaptic toxicity. Aβ induces synaptic dysfunction through the NMDA receptor by mediating PSD95 depalmitoylation and subsequent loss. Inhibition of ABHD17 depalmitoylating enzymes rescues this phenotype by increasing synaptic PSD95. C, Tau-mediated synaptic toxicity. Tau hyperphosphorylation causes its release from microtubules, which leads to its synaptic mislocalization. Together with Tau, Fyn translocates to the postsynaptic density, where they bind PSD95 and elicit excitotoxicity. This is exacerbated by Fyn palmitoylation by ZDHHC21, which tightens its connection with the PM and PSD95. D, αSyn homeostasis. αSyn inclusions retain cytosolic ERα, which reduces levels of palmitoylated ERα at the PM. αSyn also reduces MAP6 palmitoylation, disrupting vesicle trafficking. On the other hand, increasing palmitoylation of Syt-11, a vesicle protein that can alter membrane curvature, prevents αSyn inclusion formation by promoting its binding to vesicle membranes. E, mHTT aggregation. mHTT palmitoylation is decreased by ZDHHC17 inhibition and APT1 stimulation. This increases its aggregation propensity. Elevated APT1 activity may also contribute to decreased p62 palmitoylation, limiting lysosomal degradation of mHTT aggregates. Inhibition of APT1 activity rescues these phenotypes. F, mSOD mislocalization. Immature mSOD1 (before disulfide bond formation) exhibits increased palmitoylation, which causes its retention in the ER, increasing ER stress. Immature palmitoylated mSOD1 also travels to mitochondria, potentially impairing mitochondrial function. In contrast to mSOD1, the chaperone CCS, required for SOD1 maturation, is less palmitoylated in disease. CCS may direct palmitoylated mSOD1 to mitochondria, again impairing function. Throughout the figure, pathogenic pathways and protein alterations are depicted in red, while modifications that protect are shown in black. Created with BioRender.com.