Lost in traffic: consequences of altered palmitoylation in neurodegeneration

Abstract

One of the first molecular events in neurodegenerative diseases, regardless of etiology, is protein mislocalization. Protein mislocalization in neurons is often linked to proteostasis deficiencies leading to the build-up of misfolded proteins and/or organelles that contributes to cellular toxicity and cell death. By understanding how proteins mislocalize in neurons, we can develop novel therapeutics that target the earliest stages of neurodegeneration. A critical mechanism regulating protein localization and proteostasis in neurons is the protein-lipid modification S-acylation, the reversible addition of fatty acids to cysteine residues. S-acylation is more commonly referred to as S-palmitoylation or simply palmitoylation, which is the addition of the 16-carbon fatty acid palmitate to proteins. Like phosphorylation, palmitoylation is highly dynamic and tightly regulated by writers (i.e., palmitoyl acyltransferases) and erasers (i.e., depalmitoylating enzymes). The hydrophobic fatty acid anchors proteins to membranes; thus, the reversibility allows proteins to be re-directed to and from membranes based on local signaling factors. This is particularly important in the nervous system, where axons (output projections) can be meters long. Any disturbance in protein trafficking can have dire consequences. Indeed, many proteins involved in neurodegenerative diseases are palmitoylated, and many more have been identified in palmitoyl-proteomic studies. It follows that palmitoyl acyl transferase enzymes have also been implicated in numerous diseases. In addition, palmitoylation can work in concert with cellular mechanisms, like autophagy, to affect cell health and protein modifications, such as acetylation, nitrosylation, and ubiquitination, to affect protein function and turnover. Limited studies have further revealed a sexually dimorphic pattern of protein palmitoylation. Therefore, palmitoylation can have wide-reaching consequences in neurodegenerative diseases.

Refining S-acylation: Structure, regulation, dynamics, and therapeutic implications

“…The effect of S-acylation on trafficking and turnover rate is not only related to membrane partitioning but also to the interplay with ubiquitination ( Abrami et al, 2006 , 2008 ; Hach et al, 2013 ; Yount et al, 2012 ; Zaballa and van der Goot, 2018 ). S-acylation crosstalk with other modifications has been repeatedly reported ( Ahearn et al, 2011 ; Nepal et al, 2023 ; Wang et al, 2023b ; Yan et al, 2022 ), as recently reviewed ( Ramzan et al, 2023 ; Zmuda and Chamberlain, 2020 ). In the context of degradation, it occurs frequently with ubiquitination, which could be mono, multi, or polyubiquitination ( Dikic and Schulman, 2023 ).…”

Reduced S-acylation of SQSTM1/p62 in Huntington disease is associated with impaired autophagy

“…Thus, S-acylation provides an ideal mechanism for quickly redirecting proteins on and off membranes. When S-acylation is disrupted, it leads to protein mislocalization, decreased protein turnover and aggregation 5 .…”

“…The use of the tandem LC3 reporter with palmitate treatment, shows a decrease in the number of autophagosomes and an increase in autolysosomes 14 ; again indicating an overall increase in autophagy, and highlighting a link between palmitoylation and autophagy. In addition, we recently showed that the majority of autophagy regulatory genes encode a proteo form that has been detected by low- or high-throughput methods 5 , by comparing the S-acylation database SwissPalm 15 and the Autophagy Regulatory Network 16 .…”

Fatty links between multisystem proteinopathy and Small VCP-Interacting Protein.

“…Similar to myristoylation, S-acylation involves the addition of saturated fatty acids, but via a thioester bond on cysteine residues, making it labile and reversible (Ramzan et al, 2023;Zaballa & van der Goot, 2018). The 16carbon fatty acid palmitate is typically used and, therefore, this modification is more commonly referred to as Spalmitoylation or simply palmitoylation.…”