Abstract
ABSTRACTProtein palmitoylation is the most common post-translational lipid modification in the brain and is mediated by a family of 24 zDHHC enzymes. There has been growing interest in zDHHCs due to mounting evidence that these enzymes play key roles in the development and function of neuronal connections, and the fact that a number of zDHHCs have been associated with neurodevelopmental and neurodegenerative diseases. Loss-of-function variants in several zDHHCs, including zDHHC15, have been identified in patients with intellectual disabilities; however, the function of zDHHC15 in the brain has not been well studied. Here, we demonstrate that knocking down zDHHC15 in primary rat hippocampal cultures reduces dendritic outgrowth and arborization, as well as spine maturation. Moreover, knockdown of zDHHC15 reduces palmitoylation of PSD-95 and its trafficking into dendrites, resulting in an overall decrease in the density of excitatory synapses being formed onto mutant cells.
Highlights
Post-translational modification of cellular proteins by S-acylation involves the reversible attachment of fatty acids to cysteine residues and is important for the trafficking of proteins towards cell membranes and the regulation of cellular signalling (Fukata and Fukata, 2010; Ko and Dixon, 2018)
We demonstrate that knocking down zDHHC15 in primary rat hippocampal cultures reduces dendritic outgrowth and arborisation as well as spine maturation
Knockdown of zDHHC15 reduces PSD-95 palmitoylation and its trafficking into dendrites, resulting in an overall decrease in the density of excitatory synapses being formed onto mutant cells
Summary
Post-translational modification of cellular proteins by S-acylation involves the reversible attachment of fatty acids to cysteine residues and is important for the trafficking of proteins towards cell membranes and the regulation of cellular signalling (Fukata and Fukata, 2010; Ko and Dixon, 2018). 9 of the 23 genes encoding zDHHC enzymes have been associated with brain disorders and ~41% of all identified synaptic proteins are substrates for palmitoylation (Sanders et al, 2015), underscoring the importance of palmitoylation in the development and function of the brain, and in synapse biology. Despite their implied importance, little is known about the role of zDHHC enzymes in the brain and whether disrupting their enzymatic activity could contribute to brain pathology (Charollais and Van Der Goot, 2009; Fukata and Fukata, 2010; Rocks et al, 2010). Known substrates of zDHHC15 include PSD95, GAP43, SNAP25b, cysteine string protein (CSP), GABAAg2, Fyn, BACE1, CD151, cation-independent mannose 6-phosphate receptor (CIMPR) and sortillin (Fang et al, 2006; Fukata et al, 2004; Greaves et al, 2010; Greaves et al, 2008; Mill et al, 2009; Sharma et al, 2008; Tsutsumi et al, 2009; Vetrivel et al, 2009; Yokoi et al, 2016), proteins which have been shown to play an important role in the development and function of neuronal connections. zDHHC15 is one of a number of genes on the X chromosome that is duplicated in patients with intellectual disability (ID) (Linhares et al, 2016; Martinez et al, 2014), and one report has identified the loss of a zDHHC15 transcript in a female patient with non-syndromic X-linked ID (Mansouri et al, 2005)
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