Exploring the expression patterns of palmitoylating and de-palmitoylating enzymes in the mouse brain using the curated RNA-seq database BrainPalmSeq

Abstract

Protein S-palmitoylation is a reversible post-translational lipid modification that plays a critical role in neuronal development and plasticity, while dysregulated S-palmitoylation underlies a number of severe neurological disorders. Dynamic S-palmitoylation is regulated by a large family of ZDHHC palmitoylating enzymes, their accessory proteins, and a small number of known de-palmitoylating enzymes. Here, we curated and analyzed expression data for the proteins that regulate S-palmitoylation from publicly available RNAseq datasets, providing a comprehensive overview of their distribution in the mouse nervous system. We developed a web-tool that enables interactive visualization of the expression patterns for these proteins in the nervous system (http://brainpalmseq.med.ubc.ca/), and explored this resource to find region and cell-type specific expression patterns that give insight into the function of palmitoylating and de-palmitoylating enzymes in the brain and neurological disorders. We found coordinated expression of ZDHHC enzymes with their accessory proteins, de-palmitoylating enzymes and other brain-expressed genes that included an enrichment of S-palmitoylation substrates. Finally, we utilized ZDHHC expression patterns to predict and validate palmitoylating enzyme-substrate interactions.

CellPalmSeq: A curated RNAseq database of palmitoylating and de-palmitoylating enzyme expression in human cell types and laboratory cell lines

“…Depalmitoylating enzymes showed similarly enriched expression, including ABHD17A in NK cells, and ABHD17B in oligodendrocytes (Supplementary Figure S2). For the accessory proteins, GOLGA7B was highly enriched in cells of the nervous system, particularly neuronal cells, mirroring previous findings of enrichment of Golga7b in mouse neuronal cells (Supplementary Figure S2; Wild et al, 2022).…”

“…Overall, less cross study similarity was observed, highlighting the potential transcriptional heterogeneity in this cell line when derived from different sources. Unlike NIH/3T3 cells, Golga7b expression was detected in two of the three studies of PC12 cells, consistent with the neuronal expression for this accessory protein (Wild et al, 2022).…”

Synaptic activity–dependent changes in the hippocampal palmitoylome

“…6A). We previously showed that RNA expression of the ZDHHC enzymes and known depalmitoylating enzymes is highly heterogeneous across different brain regions and cell types of the nervous system ( 50 ). The high coexpression observed between enzymes or accessory proteins and the differentially palmitoylated substrates that we identified in this study suggests possible interactions that may underlie activity-dependent differential palmitoylation of these substrates after cFC.…”

Activity-dependent post-translational regulation of palmitoylating and de-palmitoylating enzymes in the hippocampus

“…Together, these data suggest that activity-dependent changes in PSD-95 palmitoylation are mediated through post-translational regulation of ZDHHC2 as opposed to regulation of ABHD17 function. We also assessed post-translational modifications of APT2, which is expressed in hippocampal neurons (Wild et al, 2022) and again found no changes in APT2 protein levels (Fig 7J; phospo-assay input, P = 0.753), palmitoylation (Fig. 7I), or phosphorylation (Fig 7J).…”

“…We chose to further study ZDHHC2 and ZDHHC5 as they have been shown to regulate activity-induced palmitoylation of synaptic proteins (Brigidi et al, 2015, 2014; Fukata et al, 2013; Noritake et al, 2009), as well as ZDHHC8 and ZDHHC9 whose function is disrupted in a subset of patients with schizophrenia (Mukai et al, 2004) and X-linked intellectual disability (Baker et al, 2015; Raymond et al, 2007), respectively. Notably, these four enzymes are highly expressed in hippocampal neurons (Wild et al, 2022), have well defined roles in regulating synaptic function and localize to neuronal dendrites and spines where they are appropriately positioned to mediate rapid, dynamic changes in the palmitoylation of synaptic proteins in response to changes in synaptic activity (Brigidi et al, 2015; Fukata et al, 2013; Shimell et al, 2019, 2021; Thomas et al, 2012, 2013; Woolfrey and Dell’Acqua, 2015).…”