Activity-Dependent Palmitoylation Controls SynDIG1 Stability, Localization, and Function

Abstract

Synapses are specialized contacts between neurons. Synapse differentiation-induced gene I (SynDIG1) plays a critical role during synapse development to regulate AMPA receptor (AMPAR) and PSD-95 content at excitatory synapses. Palmitoylation regulates the localization and function of many synaptic proteins, including AMPARs and PSD-95. Here we show that SynDIG1 is palmitoylated, and investigate the effects of palmitoylation on SynDIG1 stability and localization. Structural modeling of SynDIG1 suggests that the membrane-associated region forms a three-helical bundle with two cysteine residues located at positions 191 and 192 in the juxta-transmembrane region exposed to the cytoplasm. Site-directed mutagenesis reveals that C191 and C192 are palmitoylated in heterologous cells and positively regulates dendritic targeting in neurons. Like PSD-95, activity blockade in a rat hippocampal slice culture increases SynDIG1 palmitoylation, which is consistent with our prior demonstration that SynDIG1 localization at synapses increases upon activity blockade. These data demonstrate that palmitoylation of SynDIG1 is regulated by neuronal activity, and plays a critical role in regulating its stability and subcellular localization, and thereby its function.

Lack of BACE1 S-palmitoylation reduces amyloid burden and mitigates memory deficits in transgenic mouse models of Alzheimer’s disease

“…Notably, the dynamic synaptic localization of polytopic ionotropic glutamate receptors and many of their binding partners that lack a transmembrane domain (such as PSD-95 and GRIP2b) are regulated by palmitoylation (13-16, 52, 53). Juxtamembrane palmitoylation also contributes to dendritic spine localization of synapse differentiation-inducing gene protein 1, a type II transmembrane protein (54). Our results show that S-palmitoylation of the type I transmembrane protein BACE1 is critical for efficient localization in dendritic spines in cultured hippocampal neurons.…”

SynDIG4/Prrt1 Is Required for Excitatory Synapse Development and Plasticity Underlying Cognitive Function

“…For example, a CCFW motif in the juxta-transmembrane-associated region is conserved in all SynDIG proteins. The two cysteine residues in SynDIG1 are palmitoylated in an activity-dependent manner to regulate stability, localization, and function (Kaur et al, 2016) and preliminary experiments indicate that SynDIG4 is also palmitoylated (data not shown). It will be informative to investigate the relationship, if any, between SynDIG4 palmitoylation and its role in synapse function.…”

Functional network dynamics in a neurodevelopmental disorder of known genetic origin

“…Although multiple substrates may be relevant to neurodevelopmental disorders, one palmitoylation target is thought to be Post-Synaptic Density protein 95 (PSD-95) which is critical to activity-dependent AMPA receptor availability (El-Husseini et al, 2000a;El-Husseini et al, 2000b;Bredt et al, 2010). Palmitoylation is itself activity-dependent and influences synaptic stability across multiple timescales during development (Globa & Bamji, 2017;Kang et al, 2008;Kaur et al, 2016;Levy & Nicoll, 2017). Hence, the loss of ZDHHC9 function and reduction in palmitoylation efficiency may alter dynamic aspects of postsynaptic activity, impacting on the emergence and stability of structural and functional networks supporting cognition.…”