Abstract
ABSTRACTPalmitoylation is the most common post-translational lipid modification in the brain; however, the role of palmitoylation and palmitoylating enzymes in the nervous system remains elusive. One of these enzymes, Zdhhc5, has previously been shown to regulate synapse plasticity. Here, we report that Zdhhc5 is also essential for the formation of excitatory, but not inhibitory, synapses both in vitro and in vivo. We demonstrate in vitro that this is dependent on the enzymatic activity of Zdhhc5, its localization at the plasma membrane and its C-terminal domain, which has been shown to be truncated in a patient with schizophrenia. Loss of Zdhhc5 in mice results in a decrease in the density of excitatory hippocampal synapses accompanied by alterations in membrane capacitance and synaptic currents, consistent with an overall decrease in spine number and silent synapses. These findings reveal an important role for Zdhhc5 in the formation and/or maintenance of excitatory synapses.
Highlights
Palmitoylation is a reversible post-translational lipid modification that anchors proteins to specialized membrane domains, and can critically impact protein stability, trafficking and function (AicartRamos et al, 2011; Hannoush and Sun, 2010; Linder and Deschenes, 2007; Resh, 2006; Salaun et al, 2010)
Palmitoylation is mediated by a family of 24 Zdhhc enzymes (Braschi et al, 2019), and growing evidence suggests that Zdhhc enzymes are important for proper brain development and function
9 of the 24 Zdhhc enzymes are associated with disorders of the brain, and bioinformatics analysis has demonstrated that while 10% of all gene products are modified by palmitoylation, 41% of all synaptic proteins (Sanders et al, 2015) are substrates for palmitoylation, further amplifying the potential role for palmitoylation in synapse biology
Summary
Palmitoylation is a reversible post-translational lipid modification that anchors proteins to specialized membrane domains, and can critically impact protein stability, trafficking and function (AicartRamos et al, 2011; Hannoush and Sun, 2010; Linder and Deschenes, 2007; Resh, 2006; Salaun et al, 2010). The density of active spines was significantly reduced in cells expressing Zdhhc5 shRNA (Fig. 1I).
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